Unsaturated mTOR inhibitors

ABSTRACT

Compounds represented by Formula (I)  
                 
or a pharmaceutically acceptable salt thereof, are inhibitors of mTOR and useful in the treatment of cancer.

This application claims the benefit of U.S. Patent Application No.60/762,076, filed Jan. 25, 2006.

BACKGROUND OF THE INVENTION

The present invention is directed to bicyclic compounds that areinhibitors of mammalian Target Of Rapamycin (mTOR) kinase (also known asFRAP, RAFT, RAPT, SEP). In particular, the present invention is directedto fused bicyclic compounds that are mTOR inhibitors useful in thetreatment of cancer.

International Patent Publication WO 2001 019828 describes thepreparation of heteroaromatic amines as protein kinase inhibitors.International Patent Publication WO 2005/047289 describespyrrolopyrimidine compounds useful in treatment of cancer.

It has been shown that high levels of dysregulated mTOR activity areassociated with variety of human cancers and several hamartomasyndromes, including tuberous sclerosis complex, the PTEN-relatedhamartoma syndromes and Peutz-Jeghers syndrome. Although rapamycinanalogues are in clinical development for cancer as mTOR kinaseinhibitor, the clinical out come with CCI-779 is just modest in breastand renal cancer patients. This is probably because rapamycin partiallyinhibits mTOR function through raptor-mTOR complex (mTORC1). It has beenalso found that ⅔ of the breast cancer and 1/2 of renal cancer patientsare resistant to rapamycin therapy. With a recent discovery ofrictor-mTOR complex (mTORC2) which is involved in phosphorylation of AKT(S473) that is important in regulation of cell survival and modulationof PKCα that plays a major role in regulation of actin cytoskeletalorganization in a rapamycin-independent manner, and inhibition of theseactivities of mTOR is probably important for broader antitumor activityand better efficacy. Therefore, it is desirable to develop novelcompounds that are direct inhibitors of mTOR kinase, which would inhibitmTORC1 and mTORC2.

Rapamycin, a macrolide antibiotic has been shown to specifically inhibitmTOR kinase activity in vitro and in vivo in several studies. Althoughprecise mechanism by which rapamycin inhibits mTOR function is not wellunderstood, it is known that rapamycin first binds to FKBP12 (FK506binding protein) and then binds to FRB domain of mTOR and thus inhibitmTOR activity by inducing conformational changes, which inhibitssubstrate binding. Rapamycin has been widely used as a specific mTORinhibitor in preclinical studies to demonstrate role of mTOR in signaltransduction and cancer. But rapamycin was not developed as a cancertherapy because of stability and solubility problems even thoughsignificant antitumor activity was observed in the NCI screeningprogramme. However, synthesis of rapamycin analogues with superiorsolubility and stability properties has led to run the clinical trailswith CCI-779, RAD001 and AP23573. The most advanced rapamycin analogue,CCI-779 has shown modest anti-tumor activity in Phase II breast, renalcarcinoma and mantle cell lymphoma clinical trials.

The Tor genes were originally identified in yeast as the targets of thedrug rapamycin. The structurally and functionally conserved mammaliancounter part of yeast TOR, mTOR was later discovered. mTOR is a memberof the phosphoinositide kinase-related kinase (PIKK) family, but ratherthan phosphorylating phosphoinositides, phosphorylates proteins onserine or threonine residues. Genetic studies have shown that mTOR isessential for cell growth and development in fruit flies, nematodes andmammals, and the disruption of the genes encoding mTOR results inlethality in all species. Several studies have demonstrated that mTORhas a central role in controlling cell growth, proliferation andmetabolism. mTOR regulates a wide range of cellular functions, includingtranslation, transcription, mRNA turnover, protein stability, actincytoskeletal organization and autophagy. There are two mTOR complexes inmammalian cells. MTOR complex I (mTORC1) is a raptor-mTOR complex, whichmainly regulates cell growth in a rapamycin-sensitive manner whereasmTOR complex II (mTORC2) is a rictor-mTOR complex, which regulatescytoskeletal organization in a rapamycin-insensitive manner.

The best-characterized function of mTOR in mammalian cells is regulationof translation. Ribosomal S6 kinase (S6K) and eukaryotic initiationfactor 4E binding protein 1 (4E-BP1), the most extensively studiedsubstrates of mTOR, are key regulators of protein translation. S6K isthe major ribosomal protein kinase in mammnalian cells. Phosphorylationof S6 protein by S6K selectively increases the translation of mRNAscontaining a tract of pyrimidines motif; these mRNAs often encoderibosomal proteins and other translational regulators. Thus, S6Kenhances overall translation capacity of cells. 4E-BP1, anotherwell-characterized mTOR target, acts as a translational repressor bybinding and inhibiting the eukaryotic translation initiation factor 4E(eIF4E), which recognizes the 5′ end cap of eukaryotic mRNAs.Phosphorylation of 4E-BP1 by mTOR results in a dissociation of 4E-BP1from eIF4E, thereby relieving the inhibition of 4E-BP1 oneIF4E-dependent translation initiation. eIF4E overexpression enhancescell growth and transforms cells by increasing the translation of asubset of key growth-promoting proteins, including cyclin D1, c-Myc andVEGF. Therefore, mTOR-dependent regulation of both 4E-BP1 and S6K mightbe one mechanism by which mTOR positively regulates cell growth. mTORintegrates two of the most important extracellular and intracellularsignals involved in the regulation of cell growth: growth factors andnutrients. Growth factor, such as insulin or IGF1 and nutrients, such asamino acids or glucose, enhance mTOR function, as evidenced by anincreased phosphorylation of S6K and 4E-BP1. Rapamycin or dominantnegative mTOR inhibits these effects, indicating that mTOR integratesthe regulation of signals from growth factors and nutrients.

Signalling pathways that are upstream and downstream of mTOR are oftenderegulated in variety of cancers, including breast, lung, kidney,prostate, blood, liver, ovarian, thyroid, GI tract and lymphoma.Oncogenes including overexpressed receptor tyrosine kinases andconstitutively activated mutant receptors activate PI3K-mediatedsignaling pathways. Additional alterations of the PI3K-mTOR pathway inhuman cancers include amplification of the p110 catalytic subunit ofPI3K, loss of PTEN phosphatase function, amplification of AKT2,mutations in TSC1 or TSC2, and overexpression or amplification of eIF4Eor S6K1. Mutation or loss of heterozygosity in TSC1 and TSC2 most oftengive rise to Tuberous Sclerosis (TSC) syndrome. TSC is rarely associatedwith malignant tumors, although patients with TSC are at risk formalignant renal cancer of clear-cell histology. Although inactivation ofTSC might not lead to malignancy per se, deregulation of this pathwayseems crucial for angiogenesis in developing malignancies. TSC2regulates VEGF production through mTOR-dependent and -independentmanner.

With the recent discovery of rapamycin independent function of mTOR (bymTOR2) in phosphorylation AKT (at S473) that is important in regulationof cell survival and modulation of PKCα, which plays a major role inregulation of actin cytoskeletal organization, it is believed thatinhibition of mTOR function by rapamycin is partial. Therefore,discovery of a direct mTOR kinase inhibitor, which would completelyinhibit the function of both mTORC1 and mTORC2, is required for broaderanti-tumor activity and better efficacy. Here we describe the discoveryof direct mTOR kinase inhibitors, which can be used in the treatment ofvariety of cancers—including breast, lung, kidney, prostate, blood,liver, ovarian, thyroid, GI tract and lymphoma—and other indicationssuch as rheumatoid arthritis, hamartoma syndromes, transplant rejection,IBD, multiple sclerosis and inmunosuppression.

Recent success of Tarceva™, an EGFR kinase inhibitor for the treatmentof NSCLC and prior success with Gleevec™ for the treatment of CMLindicate that it is possible to develop selective kinase inhibitors forthe effective treatment of cancers. Although there are severalanti-cancer agents including kinase inhibitors, there is stillcontinuing need for improved anti-cancer drugs, and it would bedesirable to develop new compounds with better selectivity, potency orwith reduced toxicity or side effects.

Thus, it is desirable to develop compounds that exhibit mTOR inhibitionin order to treat cancer patients. Further, such compounds may be activein other kinases such as, for example, PI3K, Src, KDR, to add efficacyin breast, non-small cell lung cancer (NSCLC), renal cell carcinoma,mantle cell lymphoma, endometrial cancers, or other hamartoma syndromes.

SUMMARY OF THE INVENTION

Compounds represented by Formula (I)

or a pharmaceutically acceptable salt thereof, are inhibitors of mTORand useful in the treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X₁, and X₂ are each independently N or C-(E¹)_(aa);    -   X₅ is N, C-(E¹)_(aa), or N-(E¹)_(aa);    -   X₃, X₄, X₆, and X₇ are each independently N or C;        wherein at least one of X₃, X₄, X₅, X₆, and X₇ is independently        N or N-(E¹)_(aa);    -   R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, aminomethylcycloC₃₋₁₀alkyl,        bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,        heterocyclyl or heterobicycloC₅₋₁₀alkyl any of which is        optionally substituted by one or more independent G¹¹        substituents;    -   Q¹ is -A-(K)_(m)    -   A is vinyl or acetylenyl    -   K is independently, hydrogen, —N(C₀₋₈alkyl)(C₀₋₈alkyl),        hydroxyl, halogen, oxo, aryl (optionally substituted with 1 or        more R³¹ groups), hetaryl (optionally substituted with 1 or more        R³¹ groups), C₀₋₆alkyl, —C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-NR³¹¹S(O)₀₋₂R³²¹, —C₀₋₈alkyl-NR³¹¹S(O)₀₋₂NR³²¹R³³¹,        —C₀₋₈alkyl-NR³¹¹CO₂R³²¹, —C₀₋₈alkyl-CON(R³¹¹) S(O)₀₋₂R³²¹,        —C₀₋₈alkyl-S(O)₀₋₂NR³¹¹R³²¹, —C₀₋₈alkyl-NR³¹¹COR³²¹,        —C₀₋₈alkyl-NR³¹¹CONR³²¹R³³¹, —C₀₋₈alkyl-CONR³¹¹R³²¹,        —C₀₋₈alkyl-CO₂R³¹¹, —C₀₋₈alkyl-COR³¹¹, —C₀₋₈alkylS(O)₀₋₂R³¹¹,        —C₀₋₈alkyl-O—C₁₋₈alkyl, —C₀₋₈alkyl-O—C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈-alkyl-O—C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-O—C₀₋₈alkylaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,        —C₀₋₈alkylaryl, —C₀₋₈alkylhetaryl, —C₀₋₈alkylheterocyclyl,        —C₀₋₈alkyl-S—C₀₋₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylaryl, —C₀₋₈alkyl-S—C₀₋₈alkylhetaryl,        —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkyl,        —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylaryl,        —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-NR³¹¹R³²¹,        —C₂₋₈alkenyl, —C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃, OCHF₂;    -   R³¹, R³², R³³, R³¹¹, R³²¹, R³³¹, R³¹², R³²², R³³², R³⁴¹, R³¹³,        R³²³, R³³³, and R³⁴², in each instance, is independently        -   C₀₋₈alkyl optionally substituted with 1-6 independent aryl,            cyclyl, heterocyclyl, hetaryl, halo,            —CON(C₀₋₈alkyl)(C₀₋₈alkyl), —CO(C₀₋₈alkyl), —OC₀₋₈alkyl,            —Oaryl, —Ohetaryl, —Oheterocyclyl, —S(O)₀₋₂aryl,            —S(O)₀₋₂hetaryl, —S(O)₀₋₂heterocyclyl, —S(O)₀₋₂C₀₋₈alkyl,            —N(C₀₋₈alkyl)(C₀₋₈alkyl),            —N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),            —N(C₀₋₈alkyl)CO(C₁₋₈alkyl), —N(C₀₋₈alkyl)CO(C₃₋₈cycloalkyl),            —N(C₀₋₈alkyl)CO₂(C₁₋₈alkyl), —S(O)₁₋₂N(C₀₋₈alkyl)C₀₋₈alkyl),            —NR¹¹S(O)₁₋₂(C₀₋₈alkyl),            —CON(C₃₋₈cycloalkyl)(C₃₋₈cycloalkyl),            —CON(C₀₋₈alkyl)(C₃₋₈cycloalkyl),            —N(C₃₋₈cycloalkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),            —N(C₃₋₈cycloalkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),            —N(C₀₋₈alkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),            —N(C₀₋₈alkyl)CO₂(C₃₋₈cycloalkyl),            —N(C₃₋₈cycloalkyl)CO₂(C₃₋₈cycloalkyl),            S(O)₁₋₂N(C₀₋₈alkyl)(C₃₋₈cycloalkyl),            —NR¹¹S(O)₁₋₂(C₃₋₈cycloalkyl), C₂₋₈alkenyl, C₂₋₈alkynyl, CN,            CF₃, OH, or optionally substituted aryl substituents; such            that each of the above aryl, heterocyclyl, hetaryl, alkyl or            cycloalkyl groups may be optionally, independently            substituted with —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl,            halogen, oxo, aryl, hetaryl, C₀₋₆alkyl, C₀₋₈alkylcyclyl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)—S(O)₀₋₂—(C₀₋₈alkyl),            —C₀₋₈alkyl-S(O)₀₋₂—N(C₀₋₈alkyl)(C₀₋₈alkyl),            —C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),            —C₀₋₈alkyl-N(C₀₋₈alkyl)CO—N(C₀₋₈alkyl)(C₀₋₈alkyl),            —C₀₋₈alkyl-CO—N(C₀₋₈alkyl)(C₀₋₈alkyl),            —C₁₋₈alkyl-CO₂—C₀₋₈alkyl), —C₀₋₈alkylS(O)₀₋₂—(C₀₋₈alkyl),            —C₀₋₈alkyl-O—C₁₋₈alkyl, —C₀₋₈alkyl-O—C₀₋₈alkylcyclyl,            —C₀₋₈alkyl-O—C₀₋₈alkylheterocyclyl,            —C₀₋₈alkyl-O—C₀₋₈alkylaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,            —C₀₋₈alkyl-S—C₀₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylcyclyl,            —C₀₋₈alkyl-S—C₀₋₈alkylheterocyclyl,            —C₀₋₈alkyl-S—C₀₋₈alkylaryl, —C₀₋₈alkyl-S—C₀₋₈alkylhetaryl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylcyclyl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocyclyl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,            —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl, C₂₋₈alkenyl,            C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃, OCHF₂,        -   —C₀₋₈alkyl-C₃₋₈cycloalkyl,        -   —C₀₋₈alkyl-O—C₀₋₈alkyl,        -   —C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl),        -   —C₀₋₈alkyl-S(O)₀₋₂—C₀₋₈alkyl, or        -   heterocyclyl optionally substituted with 1-4 independent            C₀₋₈alkyl, cyclyl, or substituted cyclyl substituents;    -   E¹ in each instance is independently halo, —CF₃, —OCF₃, —OR²,        —NR³¹R³², —C(═O)R³¹, —CO₂R³¹, —CONR³¹R³², —NO₂, —CN,        —S(O)₀₋₂R³¹, —S(O)₀₋₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,        —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,        —NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³¹)SR³¹,        —OC(═C)OR³¹, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹,        —SC(═O)NR³¹R³², C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,        —C₁₋₁₀alkoxyC₁₋₁₀alkyl, —C₁₋₁₀alkoxyC₂₋₁₀alkenyl,        —C₁₋₁₀alkoxyC₂₋₁₀alkynyl, —C₁₋₁₀alkylthioC₁₋₁₀alkyl,        —C₁₋₁₀alkylthioC₂₋₁₀alkenyl, —C₁₋₁₀alkylthioC₂₋₁₀alkynyl,        cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, —cycloC₃₋₈alkylC₁₋₁₀alkyl,        -cycloC₃₋₈alkenylC₁₋₁₀alkyl, -cycloC₃₋₈alkylC₂₋₁₀alkenyl,        -cycloC₃₋₈alkenylC₂₋₁₀alkenyl, -cycloC₃₋₈alkylC₂₋₁₀alkynyl,        -cycloC₃₋₈alkenylC₂₋₁₀alkeynyl, -heterocyclyl-C₀₋₁₀alkyl,        -heterocyclyl-C₂₋₁₀alkenyl, or -heterocyclyl-C₂₋₁₀alkynyl, any        of which is optionally substituted with one or more independent        halo, oxo, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(═O)R³¹, —CO₂R³¹,        —C(═O)NR³¹R³², —NO₂, —CN, —S(═O)₀₋₂R³¹, —SO₂NR³¹, —NR³¹C(═O)R³²,        —NR³¹C(═O)OR³¹, —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³¹, —C(═S)OR³¹,        —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³,        —NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹, —OC(═O)NR³¹R³², —OC(═O)SR³¹,        —SC(═O)OR³¹, or —SC(═O)NR³¹R³² substituents;    -   or E¹ in each instance is independently aryl-C₀₋₁₀alkyl,        aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl,        hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, where the        attachment point is from either the left or right as written,        where any of which is optionally substituted with one or more        independent halo, —CF₃, —OCF₃, —OR³¹ , —NR³¹R³², —C(O)R³¹,        —CO₂R³¹, —C(═O)NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —S(O)₀₋₂NR³¹R³²,        —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,        —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³¹,        —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹,        —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, or —SC(═O)NR³¹R³²        substituents;    -   in the cases of —NR³¹R³², —NR³¹¹R³²¹, —NR³¹²R³²², —NR³³²R³⁴¹,        —NR³¹³R³²³, and —NR³²³R³³³, the respective R³¹ and R³², R³¹¹ and        R³²¹, R³¹² and R³²², R³³¹ and R³⁴¹, R³¹³ and R³²³, and R³²³ and        R³³³ are optionally taken together with the nitrogen atom to        which they are attached to form a 3-10 membered saturated or        unsaturated ring; wherein said ring in each instance        independently is optionally substituted by one or more        independent —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen, oxo,        aryl, hetaryl, C₀₋₆alkyl, —C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂C₀₋₈alkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂N(C₀₋₈alkyl)( C₀₋₈alkyl),        —C₀₋₈alkyl-N(C₀₋₈alkyl)CO₂(C₀₋₈alkyl),        —C₀₋₈alkyl-CON((C₀₋₈alkyl))S(O)₀₋₂(C₀₋₈alkyl),        —C₀₋₈alkyl-S(O)₀₋₂N(C₀₋₈alkyl)(C₀₋₈alkyl),        —C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),        —C₀₋₈alkyl-N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),        —C₀₋₈alkyl-CON(C₀₋₈alkyl)(C₀₋₈alkyl), —C₀₋₈alkyl-CO₂(C₀₋₈alkyl),        —C₀₋₈alkylS(O)₀₋₂(C₀₋₈alkyl), —C₀₋₈alkyl-O—C₀₋₈alkyl,        —C₀₋₈alkyl-O—C₀₋₈alkylcyclyl,        —C₀₋₈alkyl-O—C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-O—C₀₋₈alkylaryl, —Oaryl,        —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-S—C₀₋₈alkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylaryl, —C₀₋₈alkyl-S—C₀₋₈alkylhetaryl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylC₃₋₈cycloalkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocycloalkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl), C₂₋₈alkenyl, C₂₋₈alkynyl,        NO₂, CN, CF₃, OCF₃, or OCHF₂substituents; wherein said ring in        each instance independently optionally includes one or more        heteroatoms other than the nitrogen;    -   m is 0, 1, 2,or 3;    -   aa is 0 or 1; and

provided that the compound is not3-cyclobutyl-1-[(4-phenoxyphenyl)ethynyl]imidazo[1,5-α]pyrazin-8-amine,3-cyclobutyl-1-[(1-methyl-1H-imidazol-5-yl)ethynyl]imidazo[1,5-a]pyrazin-8-amine,N-{3-[(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)ethynyl]phenyl}-4-chlorobenzamideor 3-cyclobutyl-1-(pyridin-4-ylethynyl)imidazo[1,5-a]pyrazin-8-amine.

According to an aspect of the present invention, the compounds arerepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇ are C; andthe other variables are as described above for Formula I.

In an embodiment of this aspect of the present invention, the compoundsare represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is -A(K)_(m); and the other variables are as described abovefor Formula I.

According to a second aspect of the present invention, the compounds arerepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₆ and X₇ are C; and theother variables are as described above for Formula I.

In an embodiment of the second aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is -A(K)_(m); and the other variables are as described abovefor Formula I.

The compounds of the present invention include:

or a pharmaceutically acceptable salt thereof.

The present invention includes a composition comprising a compoundaccording to Formula I, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The present invention includes a composition comprising a compoundaccording to Formula I, or a pharmaceutically acceptable salt thereof;and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeuticagent.

The present invention includes a method of treatment ofhyperproliferative disorder comprising a step of administering aneffective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof.

The present invention includes a method of treatment ofhyperproliferative disorder comprising a step of administering aneffective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof, wherein the hyperproliferativedisorder is breast cancer, lung cancer, non-small cell lung cancer,kidney cancer, renal cell carcinoma, prostate cancer, cancer of theblood, liver cancer, ovarian cancer, thyroid cancer, endometrial cancer,cancer of the GI tract, lymphoma, renal cell carcinoma, mantle celllymphoma, or endometrial cancer.

The present invention includes a method of treatment of rheumatoidarthritis, hamartoma syndromes, transplant rejection, IBD, multiplesclerosis or immunosuppression diseases comprising a step ofadministering an effective amount of the compound according to FormulaI, or a pharmaceutically acceptable salt thereof.

In all of the above circumstances forbidden or unstable valences, N—S,N-halogen bonds are excluded.

As used herein, the terms C-(E¹)_(aa), and N-(E¹)_(aa) are understood torepresent ring carbon or nitrogen atoms respectively that aresubstituted by aa number of E¹ substituents.

As used herein, unless stated otherwise, “alkyl” as well as other groupshaving the prefix “alk” such as, for example, alkoxy, alkanyl, alkenyl,alkynyl, and the like, means carbon chains which may be linear orbranched or combinations thereof. Examples of alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like termsinclude carbon chains having at least one unsaturated carbon-carbonbond.

As used herein, “C₀₋₄alkyl” for example is used to mean an alkyl having0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. An alkyl having no carbon is hydrogen when the alkyl is aterminal group. An alkyl having no carbon is a direct bond when thealkyl is a bridging (connecting) group.

The terms “cycloalkyl”, “carbocyclic ring”, cyclic”, or “cyclyl”mean3-10 membered mono or polycyclic aromatic, partially aromatic ornon-aromatic ring carbocycles containing no heteroatoms, and includemono-, bi-, and tricyclic saturated carbocycles, as well as fused andbridged systems. Such fused ring systems can include one ring that ispartially or fully unsaturated, such as a benzene ring, to form fusedring systems, such as benzofused carbocycles. Cycloalkyl includes suchfused ring systems as spirofused ring systems. Examples of cycloalkyland carbocyclic rings include C₃₋₈cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthalene,adamantane, indanyl, 1,2,3,4-tetrahydronaphthalene and the like.

The term “halogen” includes fluorine, chlorine, bromine, and iodineatoms.

The term “carbamoyl” unless specifically described otherwise means—C(O)—NH— or —NH—C(O)—.

The term “aryl” is well known to chemists. The preferred aryl groups arephenyl and naphthyl.

The term “hetaryl” is well known to chemists. The term includes 5- or6-membered heteroaryl rings containing 1-4 heteroatoms chosen fromoxygen, sulfur, and nitrogen in which oxygen and sulfur are not next toeach other. Examples of such heteroaryl rings are furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term “hetaryl”includes hetaryl rings with fused carbocyclic ring systems that arepartially or fully unsaturated, such as a benzene ring, to form abenzofused hetaryl. For example, benzimidazole, benzoxazole,benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, and thelike.

Unless otherwise stated, the terms “heterocyclic ring”, “heterocycle”,“heterocyclic”, and “heterocyclyl” are equivalent, and is defined as forcyclic but also contains one or more atoms chosen independently from N,O, and S (and the N and S oxides), provided such derivatives exhibitappropriate and stable valencies. The terms include 4-8-memberedsaturated rings containing one or two heteroatoms chosen from oxygen,sulfur, and nitrogen. Examples of heterocyclic rings include azetidine,oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane,thiazolidine, oxazolidine, oxazetidine, pyrazolidine, isoxazolidine,isothiazolidine, tetrahydrothiophene, tetrahydrothiopyran, thiepane,thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane,[1,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine,thiomorpholine, and the like. Other examples of heterocyclic ringsinclude the oxidized forms of the sulfur-containing rings. Thus,tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide,thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide,tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide,thiazolidine-1-oxide, and thiazolidine-1,1-dioxide are also consideredto be heterocyclic rings. The term “heterocyclic” also includes fusedring systems, including het-het fused systems, and can include acarbocyclic ring that is partially or fully unsaturated, such as abenzene ring, to form benzofused heterocycles. For example,3,4,-dihydro-1,4-benzodioxine, tetrahydroquinoline,tetrahydroisoquinoline, isoiindoline and the like.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The invention also encompasses a pharmaceutical composition that iscomprised of a compound of Formula I in combination with apharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of FormulaI as described above (or a pharmaceutically acceptable salt thereof).

Moreover, within this preferred embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibition ofmTor, comprising a pharmaceutically acceptable carrier and a non-toxictherapeutically effective amount of compound of formula I as describedabove (or a pharmaceutically acceptable salt thereof).

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylameine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by formula I (or a pharmaceutically acceptable saltthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion, or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or a pharmaceutically acceptable salt thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial, which may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical sue such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. He suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and compositions of the present invention are useful inthe treatment of cancers of the breast, lung, kidney, prostate, blood,liver, ovarian, thyroid, GI tract and lymphoma. The compounds andcompositions are useful against cancers including non-small cell lungcancer (NSCLC), renal cell carcinoma, mantle cell lymphoma, andendometrial cancers. Further, the compounds and compositions are usefulin treating other indications such as rheumatoid arthritis, hamartomasyndromes, transplant rejection, irritable bowel disease (IBD), multiplesclerosis and immunosuppression.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, cancers of the breast, lung, kidney,prostate, blood, liver, ovarian, thyroid, GI tract and lymphoma may beeffectively treated by the administration of from about 0.01 to 50 mg ofthe compound per kilogram of body weight per day, or alternatively about0.5 mg to about 3.5 g per patient per day.

Dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kgof body weight per day are useful in the treatment of non-small celllung cancer (NSCLC), renal cell carcinoma, mantle cell lymphoma, andendometrial cancers, or alternatively about 0.5 mg to about 7 g perpatient per day. They may be treated by the administration of from about0.01 to 50 mg of the compound per kilogram of body weight per day, oralternatively about 0.5 mg to about 3.5 g per patient per day.

Dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kgof body weight per day are useful in the treatment of rheumatoidarthritis, hamartoma syndromes, transplant rejection, irritable boweldisease (IBD), multiple sclerosis and immunosuppression, oralternatively about 0.5 mg to about 7 g per patient per day. They may betreated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Biochemical Assay for Inhibiton of mTOR Activity:

The ability of compounds to inhibit the mTOR kinase activity wasdetermined in an in vitro immunoprecipitation (IP) kinase assay usingrecombinant 4E-BP1 as a substrate. The assay determines the ability ofcompounds to inhibit phosphorylation of 4E-BP1 a well-knownphysiological substrate of mTOR. The immunocapture mTOR complex fromHeLa cells is incubated with various concentrations of compounds andHis-tag 4E-BP1 in kinase assay buffer prior to addition of ATP to startthe reaction at RT. The reaction is stopped after 30 mins and thephosphorylated His-tag 4E-BP1 is captured on a Nickel-chelate plateovernight at 4° C. The phosphothreonine content of 4E-BP1 is thenmeasured using phospho-4E-BP1 (T37/46) primary antibody andcorresponding anti rabbit IgG HRP conjugated, secondary antibody. Thesecondary antibody has a reporter enzyme (eg. horseradish peroxidase,HRP) covalently attached, such that binding of primary antibody tophosphorylated 4E-BP1 can be determined quantitatively which is equal tothe amount secondary antibody bound to it. The amount of secondaryantibody can be determined by incubation with an appropriate HRPsubstrate.

The Stock Reagents used are as Follows:

Cell Lysis Buffer:

40 mM HEPES, pH 7.5 containing 120 mM NaCl, ImM EDTA, 10 mM sodiumpyrophosphate, 10 mM β-glycerophosphate, 50 mM sodium fluoride, 1.5 mMsodium vanadate and 0.3% CHAPS.

-   Complete mini EDTA-free protease inhibitors (Roche, catalog #11 836    170 001)-   HeLa cell pellets (Paragon Bioservices)-   Protein G coated plates for immunoprecipitation (Pierce, catalog    #15131)-   mTOR (aka FRAP) N-19 antibody (Santa Cruz Biotechnology, catalog    #sc-1549)    IP Wash Buffer:

50 mM HEPES, pH 7.5 containing 150 mM NaCl

Kinase Buffer:

20 mM HEPES, pH 7.5 containing 10 mM MgCl2, 4 mM MnCl2, 10 mMb-mercaptoethanol and 200 uM sodium vanadate. Make fresh for assay.

-   Recombinant 4E-BP1 (aka PHAS I) (Calbiochem, catalog #516675)

Dilute 4E-BP1 stock (1 mg/mL) 120 times in kinase assay buffer to obtaina concentration of 0.25 ug/well in 30 uL

ATP Solution

Prepare 330 uM ATP stock in kinase buffer

-   Ni-chelate Plate (Pierce, catalog #15242)    Antibody Dilution Buffer:

TBST containing 5% skim milk

Phospho-4E-BP1 (T37/46) Antibody:

1:1000 dilution of phospho-4E-BP1 (T37/46) antibody (Cell SignalingTechnology, catalog #9459) in antibody dilution buffer

Donkey Anti Rabbit IgG, HRP Conjugated

1:10,000 dilution of anti rabbit IgG HRP conjugated (GE Healthcare,Catalog #NA934) in antibody dilution buffer

HRP Substrate;

Chemiluminescent reagents (Pierce, catalog #37074)

Assay Protocol:

HeLa cell lysate was prepared in bulk by homogenizing 25 g of cellpellet in 60 mL of cell lysis buffer and then, centrifuged at 12,000 rpmfor 30 min. The clear supernatant was transferred to fresh tube,aliquoted, quickly frozen and stored at −80° C. until use.

Protein G coated 96-well plate is washed once with lysis buffer and 50μL of diluted mTOR antibody is added to each well, and incubated at RTfor 30-60 min. Then, 50 μg of HeLa cell lysate was added to each well in50 μL of lysis buffer and incubated at 4° C. in a cold room on a shakerfor 2-3 h. Lysate was removed and the plate was washed with 100 μL ofcomplete lysis buffer for 3 times. The plate was further washed 2 timeswith 100 μL of high salt wash buffer. Diluted 4E-BP1 (substrate) isadded to each well in 30 μL. The compounds were added in variousconcentrations in 5 μL to each well. The drug concentrations varied from30 μM to 0.1 μM. The final DMSO concentration was 1%. Only DMSO wasadded to positive control wells. For negative control wells, no ATPsolution was added but instead 15 μL of kinase buffer was added, thereaction was started by addition of ATP in 15 μL to a finalconcentration of 100 μM to rest of the wells except negative controlwells. The reaction was carried out for 30 min at RT. Then, 45 μL of thereaction mixture was transferred to Ni-chelate plate and incubatedovernight at 4° C. The plate was washed once with antibody dilutionbuffer and 50 μL of diluted phospho-4E-BP1 antibody was added to eachwell, and incubated at RT for 1 h. Then, the plate was washed 4 timeswith TBST and 50 μL of diluted anti-rabbit secondary antibody was addedto each plate, and incubated at RT for 1 h. The plate was washed 4 timeswith 100 μL of TBST. To each well, 50 μL of Pierce Femtochemiluminescent reagent was added and the chemiluminescence wasmeasured using victor machine.

Comparison of the assay signals obtained in the presence of compoundwith those of positive and negative controls, allows the degree ofinhibiton of phospho-4E-BP1 phosphorylation to be determined over arange of compound concentrations. These inhibiton values were fitted toa sigmoidal dose-response inhibition curve to determine the IC₅₀ values(i.e. the concentration of the compound that inhibits phosphorylation of4E-BP1 by 50%).

The EXAMPLES of this invention inhibited phosphorylation of 4E-BP1 byimmunocaptured human mTOR as determined in the above assay with IC₅₀values less than 10.00 μM.

Experimental

The following schemes, intermediates and examples serve to demonstratehow to synthesize compounds of this invention, but in no way limit theinvention. Additionally, the following abbreviations are used: Me formethyl, Et for ethyl, iPr or iPr for isopropyl, n-Bu for n-butyl, t-Bufor tert-butyl, Ac for acetyl, Ph for phenyl, 4Cl-Ph or (4Cl)Ph for4-chlorophenyl, 4Me-Ph or (4Me)Ph for 4-methylphenyl, (p-CH3O)Ph forp-methoxyphenyl, (p-NO2)Ph for p-nitrophenyl, 4Br-Ph or (4Br)Ph for4-bromophenyl, 2-CF3-Ph or (2CF3)Ph for 2-trifluoromethylphenyl, DMAPfor 4-(dimethylamino)pyridine, DCC for 1,3-dicyclohexylcarbodiimide, EDCfor 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtfor 1-hydroxybenzotriazole, HOAt for 1-hydroxy-7-azabenzotriazole, TMPfor tetramethylpiperidine, n-BuLi for n-butyllithium, CDI for1,1′-carbonyldiimidazole, DEAD for diethyl azodicarboxylate, PS-PPh3 forpolystyrene triphenylphosphine, DIEA for diisopropylethylamine, DIAD fordiisopropyl azodicarboxylate, DBAD for di-tert-butyl azodicarboxylate,HPFC for high performance flash chromatography, rt or RT for roomtemperature, min for minute, h for hour, Bn for benzyl, and LAH forlithium aluminum hydride.

Accordingly, the following are compounds that are useful asintermediates in the formation of mTOR inhibiting EXAMPLES.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were preparedaccording to the following methods. Method A was used when preparingcompounds of Formula I-AA

as shown below in Scheme 1:Method A:

where Q¹, K and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AA′, a compound ofFormula I-AAA was reacted with a suitable substituted acetylenederivative in a suitable solvent via typical Sonogashirai couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme,dioxane, dimethoxyethane, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; and chlorinated solvents suchas methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasDMF. The above process was carried out at temperatures between about−78° C. and about 120° C. Preferably, the reaction was carried outbetween 0° C. and about 50° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Alternatively,compounds of Formula I-AA″ were prepared from a compound of FormulaI-AAA by reaction with a suitable substituted vinyl derivative in asuitable solvent via typical Heck coupling procedures. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;and chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents may be used,however, the preferred solvent was DMF. The above process can be carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction was carried out between 20° C. and about 100° C.

The compounds of Formula I-AAA of Scheme 1 were prepared as shown belowin Scheme 2.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AAA, compound ofFormula II-Z was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvents were isopropanol and a mixture of THFand isopropanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 80° C. and about 120° C. The above process toproduce compounds of the present invention was preferably carried in asealed reaction vessel such as but not limited to a thick walled glassreaction vessel or a stainless steel Parr bomb. An excess amount of thereactant, ammonia, was preferably used.

The compounds of Formula II-Z of Scheme 2 were prepared as shown belowin Scheme 3.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula II-Z, intermediateIII-Z was converted to compound of Formula II-Z′. Intermediate ofFormula III-Z was treated with POCl₃ in a suitable solvent at a suitablereaction temperature. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; acetonitrile; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used. The preferred solvents included methylenechloride and acetonitrile. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 20° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. In the conversion of compound of Formula III-Z toII-Z′, suitable halogenating agent were used, but were not limited to,Br₂, I₂, Cl₂, N-chlorosuccinimide, N-bromosuccinimide, orN-iodosuccinimide. The preferred halogenating agent wasN-iodosuccinimide. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was DMF. Theabove process was carried out at temperatures between about −78° C. andabout 120° C. Preferably, the reaction was carried out between 40° C.and about 75° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired.

The compounds of Formula III-Z of Scheme 3 were prepared as shown belowin Scheme 4:

where R³ is as defined previously for compound of Formula I and A¹=OH,alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula III-Z, a compound ofFormula IV-Z and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula IV-Z and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and thelike. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used, however the preferredsolvent was methylene chloride. The above process was carried out attemperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Additionally, if compound of Formula IV-Z was a salt or bis-salt, asuitable base was required and included, but was not limited to,diisopropylethylamine or triethylamine. Alternatively, compounds ofFormula IV-Z and V (where A¹=F, Cl, Br, I) were reacted with bases suchas triethylamine or diisopropylethylamine and the like in conjunctionwith DMAP and the like. Suitable solvents for use in this processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; halogenated solvents such as chloroform or methylenechloride. If desired, mixtures of these solvents were used, however thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about −20° C. and about 40° C. Preferably,the reaction was carried out between 0° C. and 25° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially equimolar amounts of compounds of FormulaIV-Z and V (where A¹=F, Cl, Br, I) and base and substochiometric amountsof DMAP were preferably used although higher or lower amounts were usedif desired. Additionally, other suitable reaction conditions for theconversion of an amine (compound of Formula IV-Z) to an amide (compoundof Formula III-Z) can be found in Larock, R. C. Comprehensive OrganicTransformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.

The compounds of Formula IV-Z of Scheme 4 were prepared as shown belowin Scheme 5:

where A² is phthalimido or N₃.

In a typical preparation, of a compound of Formula IV-Z, a compound ofFormula VI-Z is reacted under suitable reaction conditions in a suitablesolvent. When A²=phthalimido, suitable conditions include treatment ofcompound of Formula VI-Z with hydrazine in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvent was ethanol. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VI-Z of Scheme 5 were prepared as shown belowin Scheme 6:

where A²=phthalimido or N₃.

In a typical preparation of a compound of Formula VI-Z (whenA²=phthalimido), a compound of Formula VII-Z was reacted with aphthalimide under typical Mitsunobu conditions in a suitable solvent inthe presence of suitable reactants. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN); chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasTHF. Suitable reactants for use in the above process included, but werenot limited to, triphenylphosphine and the like, and an azodicarboxylate(DIAD, DEAD, DBAD). The preferred reactants were triphenylphosphine orresin-bound triphenylphosphine (PS-PPh₃) and DIAD. The above process maybe carried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction was carried out at about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Generally, 1.0 or 1.1 equivalents oftriphenylphosphine, DIAD and phthalimide was used per equivalent ofcompound of Formula VII-Z. Additionally, compound of Formula VII-Z canbe reacted with Ts₂O, Ms₂O, Tf₂O, TsCl, MsCl, or SOCl₂ in which thehydroxy group is converted to a leaving group such as its respectivetosylate, mesylate, triflate, or halogen such as chloro and subsequentlyreacted with an amine equivalent such as NH(Boc)₂, phthalimide,potassium phthalimide or sodium azide.

The compounds of Formula VII-Z of Scheme 6 were prepared from2-chloropyrazine VIII as shown below in Scheme 7:

In a typical preparation, of a compound of Formula VII-Z, a compound ofFormula VIII was reacted under suitable reaction conditions in asuitable solvent. Suitable reaction conditions included, but were notlimited to, treating compounds of Formula VIII with a base such aslithium tetramethylpiperidide (Li-TMP) followed by treatment with areagent containing a carbonyl equivalent followed by treatment with asuitable reducing agent. Lithium tetramethylpiperidide may be preparedby reacting tetramethylpiperidine with n-butyllithium at −78° C. andwarming up to 0° C. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like. Polar solvents such as hexamethylphosphoramide(HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), andthe like may be added if necessary. If desired, mixtures of thesesolvents were used, however, the preferred solvent was THF. Suitablecarbonyl equivalent reagents include, but are not limited to, formamidessuch as DMF or suitable chloroformate such as methyl or ethylchloroformate. After addition of the suitable carbonyl equivalentreagent, the reaction if charged with a polar protic solvent such as,but not limited to, methanol or ethanol followed by treatment with asuitable reducing agent such as sodium borohydride. The above processmay be carried out at temperatures between about −80° C. and about 20°C. Preferably, the reaction was carried out at −78° C. to 0° C. Theabove process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

Both R³ and Q¹ in the compounds described herein in some instancescontain functional groups that can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups can be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 8-26 as well as in the experimentalsection but are in no way meant to limit the scope of suchtransformations. Additionally, the chemistry shown in Schemes 8-26 canalso be applied to compounds of I-AAA, II-Z, and II-Z′.

The compounds of Formula I-A (compounds of Formula I-AA whereR³=Z-CONR³¹²R³²²) were prepared as shown below in Scheme 8:

where Q¹, R³¹² and R³²² are as defined previously for compound ofFormula I and A³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A, when A³=alkyl andR³¹² and R³²² were both equal to H, reaction of compound of Formula II-A(compounds of Formula II where R³=Z-CO₂A³) with ammonia in a suitablesolvent, afforded compound of Formula I-A. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvents were isopropanol and a mixture of isopropanol/THF. The aboveprocess was carried out at temperatures between about −78° C. and about120° C. Preferably, the reaction was carried out between 80° C. andabout 120° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Additionally, in a typicalpreparation of compound of Formula I-A, compound of Formula II-A (whenA³=H) was reacted with HNR³¹²R³²² followed by ammonia in a suitablesolvent. When A³=H, typical coupling procedures include conversion ofCO₂H to COCl via treatment with SOCl₂ or oxalyl chloride followed byreaction with HR³¹²R³²² or treatment of CO₂H and HR³¹²R³²² with EDC orDCC in conjunction with DMAP, HOBT, or HOAt and the like When A³=alkylsuch as methyl or ethyl, treatment of the ester with a pre-reactedmixture of AlMe₃ and HNR³¹²R³²² afforded conversion of CO₂A³ toCO(NR³¹²R³²²). Subsequent treatment with ammonia afforded compounds ofFormula I-A.

The compounds of Formula I-A′ (compounds of Formula I-AA whereR³=Z-CO₂A³) and I-A″ (compounds of Formula I-AA where R³=Z-CO₂H) wereprepared as shown below in Scheme 9:

where Q¹ is as defined previously for compounds of Formula I andA³=alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A′, compound ofFormula II-A was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 100° C. and about 120°C. The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. In most cases, the reactions wererun in a sealed tube. Substantially equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.Typically, an excess of ammonia was used and the reaction was monitoredin order to ensure that additional of ammonia to the ester moiety didnot occur to an appreciable extent. Additionally, in a typicalpreparation of compound of Formula I-A″, compound of Formula I-A′ wasreacted under typical saponification conditions such as NaOH inTHF/H₂O/MeOH. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was amixture of THF/H₂O/MeOH. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between rt and about 60° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.

The compounds of Formula II-B (compounds of Formula II where R³=Z-CH₂OH)and I-B (compounds of Formula I-AA where R³=Z-CH₂OH) were prepared asshown below in Scheme 10:

where Q¹ is as defined previously for compound of Formula I andA³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-B, compound of FormulaII-A is treated with a suitable reducing agent such as lithium aluminumhydride or diisobutylaluminium hydride in a suitable solvent, such asTHF to afford compound of Formula II-B. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used. The preferred solvent wasTHF. The above process was carried out at temperatures between about−78° C. and about 120° C. Preferably, the reaction was carried out atapproximately −60° C. The above process to produce compounds of thepresent invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Subsequenttreatment of compound of Formula II-B under previously describedammonolysis conditions (ammonia in isopropanol in a sealed tube at 120°C.), afforded compound of Formula I-B.

The compounds of Formula II-C (compounds of Formula II whereR³=Z-CH₂A⁴), II-D (compounds of Formula II whereR³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)), I-B (compounds of Formula I-AA whereR³=Z-CH₂OH) and I-C (compounds of Formula I-AA whereR³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)) were prepared as shown below in Scheme 11:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; A⁴=suitable leaving group such as OTs, OMs, OTf, or halo suchas chloro, bromo, or iodo and A⁵=N, O or S.

In a typical preparation of compound of Formula I-C, the hydroxy groupof compound of Formula II-B was converted to a suitable leaving group,A⁴, such as Cl or OTs, OMs, or OTf, by reaction with SOCl₂ or Ts₂O,Ms₂O, or Tf₂O to afford compound of Formula II-C. Reaction of compoundof Formula II-C with HA⁵(R³¹³)(R³²³)_(aa) afforded compound of FormulaII-D. Subsequent reaction of compound of Formula II-D under previouslydescribed ammonolysis conditions afforded compound of Formula I-C.Additionally, compound of Formula II-B was converted to compound ofFormula I-B as described previously in Scheme 10. Further conversion ofcompound of Formula I-B to compound of Formula I-C was accomplished byfollowing the previously described conditions for the conversion ofcompound of Formula II-B to compound of Formula II-C and the furtherconversion of compound of Formula II-C to compound of Formula II-D (inthe net conversion of OH to A⁵(R³¹³)(R³²³)_(aa)). Furthermore, compoundof Formula II-B can be directly converted to compound of Formula II-D bytreating compound of Formula II-B with various alkylating agent or withphenols via the Mitsunobu reaction to afford compounds Formula II-D(compounds of Formula II where R³═CH₂-Z-A⁵(R³¹³)(R³²³)_(aa)) in whichA⁵=O, aa=0, and R³¹³=alkyl or aryl).

The compounds of Formula I-C′ (compounds of Formula I-AA whereR³=Z-CH₂-A²), I-C″ (compounds of Formula I-AA where R³=Z-CH₂—NH₂), andI-C′″ (compounds of Formula I-AA where R³=Z-CH₂—N(R³¹³)(R³²³)) wereprepared as shown below in Scheme 12:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I and A²=phthalimido or N₃.

In a typical preparation of compounds of Formula I-C′, I-C″, and I-C′″,the hydroxy group of compound of Formula I-B was converted to A²,following the procedures as described in Scheme 11 for the conversion ofcompound of Formula II-B to compound of Formula II-C. Reaction ofcompound of Formula I-C′ under conditions also described in Scheme 11afforded compound of Formula I-C″. Reaction of compound of Formula I-C″with, but not limited to various alkylating agents, variousaldehydes/ketones under reductive animation conditions, variousacylating agents such as acetic anhydride, benzoyl chlorides, or withcarboxylic acids in the presence of EDC or DCC with HOBT or HOAT, orwith sulphonylating agents such as Ts₂O or MeSO₂Cl afforded compounds ofFormula I-C′″. For example, in a typical preparation of compounds ofFormula I-C′″, a compound of Formula I-C″ is treated with a suitableacylating agent in the presence of a suitable base in a suitablesolvent. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was chloroform. Suitable bases for use inthe above process included, but were not limited to, trialkylamines suchas diisopropylethylamine, triethylamine, or resin bound trialkylaminessuch as PS-DIEA. The preferred base was PS-DIEA. In the case where thesuitable acylating agent was acetic anhydride, the conversion ofcompound of Formula I-C″ to compound of Formula I-C′″ where R³¹³═H andR³²³═COCH₃ was accomplished. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 0° C. and about 20° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula I-D (compounds of Formula I-AA whereR³═(CH₂)_(n)-Z²-H and Z² is a heterocyclyl ring containing a nitrogenatom connected to H) and I-E (compounds of Formula I-AA whereR³═(CH₂)_(n)-Z²-R³¹ and Z² is a heterocyclyl ring containing a nitrogenatom connected to R³¹) were prepared as shown below in Scheme 13:

where Q¹ and R³¹ are as defined previously for compound of Formula I,G^(99a) is C(═O)A⁶ or CO₂A⁶, n=0-5, and A⁶=alkyl, aryl, or aralkyl.

In a typical preparation of compound of Formula I-E, compound of FormulaII-E is treated with suitable reagents capable of converting N-G^(99a)to N—H and therefore afford compound of Formula I-D. For example,treatment of compound of Formula II-E (when G^(99a) is equal to CO₂Bn)under previously described ammonolysis conditions followed by treatmentwith concentrated HCl and a suitable basic workup, affords compound ofFormula I-D. Compound of Formula I-D can be subjected to variousconditions including but not limited to reductive animations,alkylations and ar(hetar)ylations, and acylations to afford amides,ureas, guanidines, carbamates, thiocarbamates, sulphonamides, andvariously substituted nitrogen adducts to afford the net conversion ofNH to NR².

The compounds of Formula II-G (compounds of Formula II where R³=Z³-OH),II-H (compounds of Formula II where R³=Z-A⁵(R³¹³)(R323)_(aa)) , I-F(compounds of Formula I-AA where R³=Z-OH), and I-G (compounds of FormulaI-AA where R³=Z-A⁵(R³¹³)(³²³)_(aa)) were prepared as shown below inScheme 14:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; aa=0 or 1; and A⁵=N, O or S.

In a typical preparation of compound of Formula I-F and I-G, thefollowing transformations occurred: Compound of Formula II-F was reducedwith a suitable reducing agent that would selectively reduce thecarbonyl system over the unsaturated Q¹ group, in a suitable solvent,such as sodium borohydride in methanol to afford compound of FormulaII-G. Compound of Formula II-G was subjected to previously describedammonolysis conditions to afford compound of Formula I-F. Additionally,compounds of Formula II-F can be reacted with various amines underreductive animation conditions (NaBH₃CN or NaBH(OAc)₃ withHA⁵(R³¹³)(R³²³)_(aa) where d=0, A⁵=N, and R³¹³ and R³²³ are aspreviously described for compound of Formula I) to afford compounds ofFormula II-H where d=0, A⁵=N, and R³¹³ and R³²³ are as previouslydescribed for compound of Formula I. Subsequent reaction of compounds ofFormula II-H (compounds of Formula II where R³=Z-A⁵(R³¹³)(R³²³)_(aa)where d=0, A⁵=N, and R³¹³ and R³²³ are as previously described forcompound of Formula I) with previously described ammonolysis conditionsafforded compounds of Formula I-G. Furthermore, compounds of FormulaII-H from II-G and I-G from I-F can be synthesized according to theconditions described in Scheme 11 for the transformations of II-B toII-D and I-B to I-C, respectively.

The compounds of Formula I-L (compounds of Formula I-AA whereR³=Z-NR³¹³R³²³) were prepared as shown below in Scheme 15:

where Q¹, R³¹² and R³²² are as defined previously for compound ofFormula I.

Compounds of Formula II-F (compounds of Formula II where R³=Z=O) weretreated under typical reductive animation conditions, involving asuitable amine, HNR³¹²R³²² and a suitable reducing agent, such as butnot limited to, NaBH(OAc)₃ or NaBH(CN)₃, affording compound of FormulaII-M (compounds of Formula II where R³=Z-NR³¹²R³²²). Compound of FormulaII-M (compounds of Formula II where R³=Z-NR³¹²R³²²) was treated underammonolysis conditions, ammonia in isopropanol in a stainless steel bombat 110° C., to afford compound of Formula I-L (compounds of Formula I-AAwhere R³=Z-NR³¹²R³²²).

The compounds of Formula I-O (compounds of Formula I whereR³=Z³-OH(G¹¹)) were prepared as shown below in Scheme 16:

where Q¹ and G¹¹ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I-O (compounds ofFormula I where R³=Z-OH(G¹¹)), the ketone moiety of compound of FormulaII-F (compounds of Formula II where R³=Z=O) was reacted with a suitablenucleophilic reagent such as MeMgBr or MeLi in a suitable solvent suchas THF to afford compound of Formula II-N (compounds of Formula II whereR³=Z-OH(G¹¹)). Compound of Formula II-N (compounds of Formula II whereR³=Z-OH(G¹¹)) was reacted under ammonolysis conditions, ammonia inisopropanol in a stainless steel bomb at 110° C., to afford compound ofFormula I-O (compounds of Formula I where R³=Z-OH(G¹¹)).

The compounds of Formula I-R (compounds of Formula I-AA where R³=aryl orheteroaryl) were prepared as shown below in Scheme 17:

A compound of Formula IV-Z can be reacted with methyl chlorothiolformatein the presence of a base in a suitable solvent to afford a compound offormula III-Z (R³═SMe). Suitable solvents for this process included, butwere not limited to ethers such as tetrahydrofuran (THF), glyme,dioxane, dimethoxyethane, and the like; dimethylformamide (DMF) andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction was carried out between 0° C. and 50° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.The conversion of compounds of Formula III-Z (R³═SMe) into compounds ofFormula I-PP′ was conducted using procedures described for the relatedconversions in Scheme 3.

The conversion of compounds of Formula I-PP′ to compounds of FormulaI-RR may be accomplished by reaction with a boronic acid ester usingso-called “Liebeskind-Srogl” conditions such as those described inOrganic Letters, (2002), 4(6), 979 or Synlett, (2002), (3), 447. Suchreactions can be performed selectively at the thiomethyl group even inthe presence of halogen substituents such as iodo or bromo.

A compound of Formula I-AB is equal to compound of Formula I whereinX₁═CH, X₂, X₄ and X₅═N, and X₃, X₆ and X₇═C; Q¹ is as defined for acompound of Formula I; R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,aminomethylcycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl,spiroalkyl, or heterospiroalkyl, any of which is optionally substitutedby one or more independent G¹¹ substituents; and G¹¹ is as defined for acompound of Formula I:

Method AB was used when preparing compounds of Formula I-AB as shownbelow in Scheme 18:Method AB:

where Q¹, K and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AB′, a compound ofFormula I-ABA may be reacted with a suitable substituted acetylenederivative in a suitable solvent via typical Sonogashirai couplingprocedures. Suitable solvents for use in the above process include, butare not limited to, ethers such as tetrahydrofuran (THF), glyme,dioxane, dimethoxyethane, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; and chlorinated solvents suchas methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents may be used, however, the preferred solventis DMF. The above process may be carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction is carried outbetween 0° C. and about 50° C. The above process to produce compounds ofthe present invention may be preferably carried out at about atmosphericpressure although higher or lower pressures can be used if desired.Substantially equimolar amounts of reactants are preferably usedalthough higher or lower amounts can be used if desired. Alternatively,compounds of Formula I-AB″ may be prepared from a compound of FormulaI-ABA by reaction with suitable substituted vinyl derivatives in asuitable solvent via typical Heck coupling procedures. Suitable solventsfor use in the above process include, but are not limited to, etherssuch as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;and chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents may be used,however, the preferred solvent is DMF. The above process can be carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction is carried out between 20° C. and about 100° C.

The compounds of Formula I-ABA wherein R³ is C₁₋₁₀alkyl,cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents, of Scheme 18 were prepared as shown below in Scheme 19:

where R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I, and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula I-ABA, a compound ofFormula I-ABB was reacted with an alcohol R³—OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was THF. Suitable reactants for use inthe above process included, but were not limited to, triphenylphosphineand the like, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DIAD, and R³—OH was used perequivalent of compound of Formula I-ABB.

Alternatively, the compounds of Formula I-ABA may be prepared byalkylating compounds of Formula I-ABB with an alkylating agent R³-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

Preferably, in compounds of Formula I-ABB, A¹¹=Br and I. These compoundsare known (A¹¹=I: H. B. Cottam et al., J. Med. Chem. 1993, 36(22),3424-3430; A¹¹=Br: T. S. Leonova et al., Khim. Geterotsikl. Soedin.1982, (7), 982-984).

Compound of Formula I-AC is equal to compound of Formula I wherein X₁and X₅═CH, X₂ and X₄═N, and X₃, X₆ and X₇═C; Q¹ is as defined for acompound of Formula I; R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents; and G¹¹ is as defined for a compound of Formula I:

Method AC was used when preparing compounds of Formula I-AC as shownbelow in Scheme 20:Method AC:

where Q¹, K and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AC′, a compound ofFormula I-ACA may be reacted with a suitable substituted acetylenederivative in a suitable solvent via typical Sonogashirai couplingprocedures. Suitable solvents for use in the above process include, butare not limited to, ethers such as tetrahydrofuran (THF), glyme,dioxane, dimethoxyethane, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; and chlorinated solvents suchas methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents may be used, however, the preferred solventis DMF. The above process may be carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction is carried outbetween 0° C. and about 50° C. The above process to produce compounds ofthe present invention may be preferably carried out at about atmosphericpressure although higher or lower pressures can be used if desired.Substantially equimolar amounts of reactants are preferably usedalthough higher or lower amounts can be used if desired. Alternatively,compounds of Formula I-AC″ may be prepared from a compound of FormulaI-ACA by reaction with suitable substituted vinyl derivatives in asuitable solvent via typical Heck coupling procedures. Suitable solventsfor use in the above process include, but are not limited to, etherssuch as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;and chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents may be used,however, the preferred solvent is DMF. The above process can be carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction is carried out between 20° C. and about 100° C.

The compounds of Formula I-ACA of Scheme 20 were prepared as shown belowin Scheme 21:

where R³ is as defined previously for compound of Formula I-AC, andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-ACA, compound ofFormula XV was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out in a glass pressure tube or a stainless steelreactor. Preferably, an excess of ammonia was used.

The compounds of Formula XVA (=compounds of Formula XV of Scheme 21wherein R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloCs₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 22:

where R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula XVA, a compound ofFormula XVI was reacted with an alcohol R³—OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was THF. Suitable reactants for use inthe above process included, but were not limited to, triphenylphosphineand the like, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DLAD, and R³—OH was used perequivalent of compound of Formula XVI.

Alternatively, the compounds of Formula XVA may be prepared byalkylating compounds of Formula XVI with an alkylating agent R³-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

The compounds of Formula XVB (=compounds of Formula XV of Scheme 21wherein R³ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 23:

where R³ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents, G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula XVB, compound ofFormula XVI was reacted with a suitable boronic acid of FormulaR³—B(OH)₂ in a suitable solvent via typical copper(II)-mediated couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme,1,4-dioxane, and the like; dimethylformamide (DMF);N-methylpyrrolidinone (NMP); chlorinated solvents such as methylenechloride (CH₂Cl₂). If desired, mixtures of these solvents were used,however, the preferred solvent was methylene chloride (CH₂Cl₂). Suitablereactants for use in the above process included, but were not limitedto, copper(II) acetate (Cu(OAc)₂), copper(II) triflate (Cu(OTf)₂), andthe like, and a base (pyridine, and the like). The preferred reactantswere Cu(OAc)₂ and pyridine. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure under air, although higher or lower pressures could be used ifdesired. Preferably, the reaction was carried out at about 22° C.Generally, 1.5eq. of copper(II) acetate, 2eq. of pyridine, and 2eq. ofboronic acid of Formula R³—B(OH)₂ were used per equivalent of compoundof Formula XVI.

All compounds of Formula XVI are known in the literature (A¹¹=I: L. B.Townsend et al., J. Med. Chem. 1990, 33, 1984-92; A¹¹=Br, Cl: L. B.Townsend et al., J. Med. Chem. 1988, 31, 2086-2092). Preferably, A¹¹=Brand I.

Both R³ and Q¹ in the compounds described herein in some instancescontain functional groups that can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups could be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 24-25 as well as in theexperimental section but are in no way meant to limit the scope of suchtransformations.

The compounds of Formula I-ACA′ (=compounds of Formula I-ACA whereR³=Z-CONR³¹²R³²²) were prepared from compounds of Formula XV′(=compounds of Formula XV where R³=Z-CO₂A³) as shown below in Scheme 24:

where R³¹² and R³²² are as defined previously for compound of Formula I;A¹¹=halogen such as Cl, Br, or I; and A³=hydrogen or alkyl such asmethyl or ethyl.

In a typical preparation of compound of Formula I-ACA′, when A³=alkyland R³¹² and R³²² were both equal to H, reaction of compound of FormulaXV′ with ammonia in a suitable solvent, afforded compound of FormulaI-ACA′. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent wasisopropanol. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 80° C. and about 100° C. The above process to produce compoundsof the present invention was preferably carried out in a glass pressuretube or a stainless steel reactor. Preferably, an excess of ammonia wasused. Additionally, in a typical preparation of compound of FormulaI-ACA′ (compounds of Formula I-ACA where R³=Z-CONR³¹²R³²²), compound ofFormula XV′ (compounds of Formula XV′ where R³=Z-CO₂A³) was reacted withHNR³¹²R³²² followed by ammonia in a suitable solvent. When A³=H, typicalcoupling procedures (such as conversion of —CO₂H to —COCl via treatmentwith SOCl₂ or oxalyl chloride followed by reaction with HNR³¹²R³²² ortreatment of —CO₂H and HNR³¹²R³²² with EDC or DCC in conjunction withDMAP, HOBT, or HOAt and the like) were employed to afford thetransformation of a carboxylic acid to an amide. When A³=alkyl such asmethyl or ethyl, treatment of the ester with Al(NR³¹²R³²²) affordedconversion of —CO₂A³ to —CO(NR³¹² H³²²). Subsequent treatment withammonia afforded compounds of Formula I-ACA′.

The chemistry shown in Scheme 24 can also be applied to compounds withQ¹ in place of A¹¹.

The compounds of Formula XVIII (compounds of Formula XV, I-ACA, or I-ACwhere R³=Z-CH₂OH), XIX (compounds of Formula XV, I-ACA, or I-AC whereR³=Z-CH₂LG), and XX (compounds of Formula XV, I-ACA, or I-AC whereR³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)) were prepared as shown below in Scheme 25:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; LG=suitable leaving group such as tosylate, mesylate,trifluoromethanesulfonate, or halo such as chloro, bromo, or iodo; aa=0or 1; A³=hydrogen or alkyl such as methyl or ethyl; A¹¹=halogen such asCl, Br, or I; A¹²=Cl or NH₂; A¹³=A¹¹ or Q¹; and A⁵=N, O or S.

The following table indicates the relations between the compounds ofFormulas XVII-XX, A¹², A¹³, compounds of Formulas I-AC, I-ACA, and XV,and R³. Compound of wherein . . . is equal to Formula . . . A¹² = andA¹³ = Formula . . . wherein R³ = XVII Cl A¹¹ XV Z-CO₂A³ XVII NH₂ A¹¹I-ACA Z-CO₂A³ XVII NH₂ Q¹ I-AC Z-CO₂A³ XVIII Cl A¹¹ XV Z-CH₂OH XVIII NH₂A¹¹ I-ACA Z-CH₂OH XVIII NH₂ Q¹ I-AC Z-CH₂OH XIX Cl A¹¹ XV Z-CH₂LG XIXNH₂ A¹¹ I-ACA Z-CH₂LG XIX NH₂ Q¹ I-AC Z-CH₂LG XX Cl A¹¹ XVZ-CH₂A⁵R²(R⁴)_(d) XX NH₂ A¹¹ I-ACA Z-CH₂A⁵R²(R⁴)_(d) XX NH₂ Q¹ I-ACZ-CH₂A⁵R²(R⁴)_(d)

In a typical preparation of compound of Formula XVIII (compounds ofFormula XV, I-ACA, or I-AC, where R³=Z-CH₂OH), compound of Formula XVII(compounds of Formula XV, I-ACA, or I-AC, where R³=Z-CO₂A³) is treatedwith a suitable reducing agent, such as lithium aluminum hydride ordiisobutylaluminum hydride, in a suitable solvent, such as THF ormethylene chloride, to afford compound of Formula XVIII. In a typicalpreparation of compound of Formula XX (compounds of Formula XV, I-ACA,or I-AC, where R³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)), the hydroxy group ofcompound of Formula XVIII was converted to a suitable leaving group, LG,such as Cl or tosylate, mesylate, or triflate, by reaction with SOCl₂ orTs₂O, Ms₂O, or Tf₂O to afford compound of Formula XIX (compounds ofFormula XV, I-ACA, or I-AC, where R³=Z-CH₂LG). Reaction of compound ofFormula XIX with HA⁵(R³¹³)(R³²³)_(aa) afforded compound of Formula XX.Furthermore, compound of Formula XVIII can be directly converted tocompound of Formula XX by treating compound of Formula XVIII withvarious alkylating agents or under typical Mitsunobu reaction conditionsto afford compounds of Formula XX (compounds of Formula XV, I-ACA, orI-AC, where R³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)) in which A⁵=O, aa=0, andR³¹³=alkyl or aryl). Someone skilled in the art will choose the mostappropriate stage during the sequence shown in Scheme 25 to convertA¹²=Cl to A¹²=NH₂ as described in Scheme 21, and to convert A¹³=A¹¹ toA¹³=Q¹ as described in Scheme 20, if applicable.

An alternative preparation of compounds of Formula I-AC is shown inScheme 26.

where Q¹ and R³ are as defined previously for compound of Formula I; andA¹¹=halogen such as Cl, Br, or I.

The compounds of Formula XXI may be prepared from aldehydes Q¹-CHO (seeScheme 14 for their preparation) by addition of methyllithium or amethyl Grignard reagent, followed by oxidation of the resulting alcoholto the ketone of Formula XXI. Other compounds are commercially availableor can be prepared by methods well known to someone skilled in the art,see: Larock, R. C. Comprehensive Organic Transformations, 2^(nd) ed.;Wiley and Sons: New York, 1999, 1197ff. Reaction of compounds of FormulaXXI under typical halogenation conditions with typical halogenatingagents including, but not limited to, Br₂, NBS, pyridinium perbromide,or CuBr₂ (for A¹¹=Br), or NCS or SO₂Cl₂ (for A¹¹=Cl) gives the compoundsof Formula XXII. Their reaction with amines of Formula H₂N—R³ gives theaminoketones of Formula XXIII that are converted to aminocyanopyrrolesof Formula XXIV by reaction with malononitrile under basic conditions.Finally, reaction of compounds of Formula XXIV under typical cyclizationconditions gives the compounds of Formula I-AC. Conditions for thiscyclization include, but are not limited to, heating with formamide;heating with formamide and ammonia; sequential treatment with a trialkylorthoformate, ammonia, and a base; sequential treatment with formamidineand ammonia.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Compound of Formula I-AQ is equal to compound of Formula I whereinX₁═CH; X₂, X₃ and X₅═N; X₄, X₆, and X₇═C and J=H or NH₂

Method AQ was used when preparing compounds of Formula I-AQ as shownbelow in Scheme 27:Method AQ:

where Q¹, K and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I and J=H or NH₂.

In a typical preparation of compounds of Formula I-AQ′, a compound ofFormula II-Q may be reacted with a suitable substituted acetylenederivative in a suitable solvent via typical Sonogashirai couplingprocedures. Suitable solvents for use in the above process include, butare not limited to, ethers such as tetrahydrofuran (THF), glyme,dioxane, dimethoxyethane, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; and chlorinated solvents suchas methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents may be used, however, the preferred solventis DMF. The above process may be carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction is carried outbetween 0° C. and about 50° C. The above process to produce compounds ofthe present invention may be preferably carried out at about atmosphericpressure although higher or lower pressures can be used if desired.Substantially equimolar amounts of reactants are preferably usedalthough higher or lower amounts can be used if desired. Alternatively,compounds of Formula I-AQ″ may be prepared from a compound of FormulaII-Q by reaction with suitable substituted vinyl derivatives in asuitable solvent via typical Heck coupling procedures. Suitable solventsfor use in the above process include, but are not limited to, etherssuch as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;and chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents may be used,however, the preferred solvent is DMF. The above process can be carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction is carried out between 20° C. and about 100° C.

The compounds of Formula II-Q of Scheme 27 were prepared as shown belowin Scheme 28.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I; and J=H or NH₂.

In a typical preparation of compounds of Formula II-Q, compound ofFormula III-Q was reacted with phosphorus oxychloride (POCl₃) andtriazole, and pyridine followed by ammonia (NH₃) in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −20° C. and about 50° C.Preferably, the reaction was carried out between 0° C. and about 25° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III-Q of Scheme 28 were prepared as shown belowin Scheme 29.

where R³ is as defined previously for compound of Formula I; A¹¹=halogensuch as Cl, Br, or I; and J=H or NH₂.

In a typical preparation of a compound of Formula III-Q, intermediateV-Q was converted to compound of Formula IV-Q. Intermediate of FormulaV-Q was treated with phosphorus oxychloride (POCl₃) in a suitablesolvent at a suitable reaction temperature. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like, chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃), and acetonitrile. Ifdesired, mixtures of these solvents were used. The preferred solvent wasacetonitrile. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 40° C. and about 95° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Intermediate for Formula III-Q was prepared by reacting intermediate ofFormula IV-Q with a suitable halogenating agent. Suitable halogenatingagents included, but were not limited to, Br₂, I₂, Cl₂,N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. Thepreferred halogenating agent was N-iodosuccinimide. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; dimethylformamide(DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcohols such asmethanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was DMF. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 75° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

Compounds of Formulae IV-Q and III-Q where J=NH₂ can be respectivelyconverted into the compounds of Formulae IV-Q and III-Q where J=H, bydiazotisation procedures known to those skilled in the art. A typicalprocedure includes the treatment of a compound of Formula IV-Q or III-Qwhere J=NH₂ with tert-butylnitrite in a suitable solvent such a THF orDMF.

The compounds of Formula V-Q of Scheme 29 were prepared as shown belowin Scheme 30:

where R¹ is as defined previously for compound of Formula I; A¹=OH,alkoxy, or a leaving group such as chloro, imidazole or O-succinimide;and J=H or NH₂.

In a typical preparation, of a compound of Formula V-Q, a compound ofFormula VI-Q and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula VI-Q and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and thelike, or reagents like EEDQ. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such aschloroform or methylene chloride. If desired, mixtures of these solventswere used, however the preferred solvent was methylene chloride. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Alternatively, compounds of Formula VI-Q and V (whereA¹=F, Cl, Br, I) were reacted with bases such as triethylamine ordiisopropylethylamine and the like in conjunction with DMAP and thelike. Suitable solvents for use in this process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;pyridine; halogenated solvents such as chloroform or methylene chloride.If desired, mixtures of these solvents were used, however the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −20° C. and about 40° C. Preferably, the reaction wascarried out between 0° C. and 25° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of compounds of Formula VI-Qand V (where A¹=F, Cl, Br, I) and base and substochiometric amounts ofDMAP were preferably used although higher or lower amounts were used ifdesired. Additionally, other suitable reaction conditions for theconversion of an amine (compound of Formula VI-Q) to an amide (compoundof Formula V-Q) can be found in Larock, R. C. Comprehensive OrganicTransformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, pp1941-1949.

The compounds of Formula VI-Q of Scheme 30 where J=H were prepared asshown below in Scheme 31:

In a typical preparation, of a compound of Formula VI-Q, a compound ofFormula VII-Q is reacted under suitable reaction conditions in asuitable solvent. Suitable conditions include treatment of compound ofFormula VII-Q with hydrazine or methyl hydrazine in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvents were ethanol andmethylene chloride. The above process was carried out at temperaturesbetween about 0° C. and about 80° C. Preferably, the reaction wascarried out at about 22° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired.

Compounds of Formula VI-Q where J=NH₂ may be prepared according to theprocedures described in J. Het. Chem., (1984), 21, 697.

The compounds of Formula VII-Q of Scheme 31 were prepared as shown belowin Scheme 32:

In a typical preparation of a compound of Formula VII-Q, a compound ofFormula VIII-Q was reacted with Raney Nickel in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformarnide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out at about 80° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Additionally a compound of Formula VII-Q can beprepared by reacting a compound of Formula VIII-Q with a suitableoxidizing agent in a suitable solvent. A suitable oxidizing agentincludes, but is not limited to hydrogen peroxide (H₂O₂), 3-chloroperoxybenzoic acid (mCPBA) and the like. Suitable solvents for use inthe above process included, but were not limited to, ethers such as THF,glyme, and the like; DMF; DMSO; CH₃CN; and dimethylacetarnide (DMA);chlorinated solvents such as CH₂Cl₂ or CHCl₃ If desired, mixtures ofthese solvents were used, however, the preferred solvent was DMA. Theabove process may be carried out at temperatures between about 0° C. and100° C. Preferably, the reaction was carried out at about rt to 70° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VIII-Q of Scheme 32 were prepared as shownbelow in Scheme 33:

In a typical preparation of a compound of Formula VIII-Q, a compound ofFormula IX-Q was reacted with thiosemicarbazide and a suitable base in asuitable solvent. Suitable bases include, but were not limited totriethylamine, diisopropylethylamine and the like. Suitable solvents foruse in the above process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out between about 40°C. and 80° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Compound of Formula IX-Q can beprepared according to literature procedures Knutsen, Lars J. S. et. al.,J. Chem. Soc. Perkin Trans 1: Organic and Bio-Organic Chemistry(1972-1999), 1984, 229-238.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Method AW was also used when preparing compounds of Formula II-Q asshown below in Scheme 34:Method AW:

where Q¹ and R³ are as defined previously for compound of Formula I, andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula II-Q, compound ofFormula III-W was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like; alcohols suchas methanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was isopropanol. The above process was carried out attemperatures between about 0° C. and about 50° C. Preferably, thereaction was carried out at between 0° C. and about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III-W of Scheme 34 were prepared as shown belowin Scheme 35.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula III-W, compound V—Wwas converted to compound of Formula IV-W. Compound of Formula V-W wastreated with phosphorus oxychloride (POCl₃) or the isolated “Vilsmeirsalt” [CAS #33842-02-3] in a suitable solvent at a suitable reactiontemperature. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like, chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃), and acetonitrile (CH₃CN). If desired, mixtures ofthese solvents were used. The preferred solvent was acetonitrile. Theabove process was carried out at temperatures between about −78° C. andabout 120° C. Preferably, the reaction was carried out between 40° C.and about 95° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Compounds ofFormula III-W were prepared by reacting compound of Formula IV-W with asuitable halogenating agent. Suitable halogenating agents included, butwere not limited to, Br₂, I₂, Cl₁₂, N-chlorosuccinimide,N-bromosuccinimide, or N-iodosuccinimide. The preferred halogenatingagent was N-iodosuccinimide. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 40° C. and about 75° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.

The compounds of Formula V-W of Scheme 35 were prepared as shown belowin Scheme 36.

where R³ is as defined previously for compound of Formula I, X¹²=azido,or mono- or di-protected amino and A¹=OH, alkoxy or a leaving group suchas chloro or imidazole.

In a typical preparation of a compound of Formula V-W, compound VI-W wasreacted with compound V under suitable amide coupling conditions.Suitable conditions include but are not limited to those described forthe conversion of compound XIII to compound XII as shown in Scheme 10.Compounds of Formula VI-W were prepared from compounds of Formula VII-W.A typical procedure for the conversion of compounds of Formula VII-W tocompounds of Formula VI-W involves subjecting a compound of FormulaVII-W, where X¹²=azido, to reducing conditions such as, but not limitedto, catalytic hydrogenation in a suitable solvent at a suitable reactiontemperature. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like, alcoholic solvents such as methanol, ethanol and the like,esters such as ethyl acetate, methyl acetate and the like. If desired,mixtures of these solvents were used. The preferred solvents were ethylacetate and methanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 40° C. and about 95° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Alternatively, when X¹²=azido, the reduction to compounds ofFormula VI-W could be achieved by treatment of a compound of FormulaVII-W with triaryl- or trialkylphosphines in the presence of water in asuitable solvent at a suitable reaction temperature. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), dioxane and the like, alcoholic solventssuch as methanol, ethanol and the like, esters such as ethyl acetate,methyl acetate and the like, DMF, acetonitrile, and pyridine. Ifdesired, mixtures of these solvents were used. The preferred solventswere THF and acetonitrile. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired.

Where X¹²=mono- or di-protected amino, the deprotection could beeffected by the procedures known to those skilled in the art and asdisclosed in: “Protective Groups in Organic Syntheses”, T. W. Greene andP. G. M. Wuts, John Wiley and Sons, 1989.

The compounds of Formula VII-W of Scheme 36 were prepared as shown belowin Scheme 37:

where R₃ is as defined previously for compound of Formula I, X¹² is asdefined for a compound of Formula VII-W and A¹²=iodo, bromo, chloro,tosylate, mesylate or other leaving group.

In a typical preparation of a compound of Formula VII-W where X¹²=azide,compound VIII-W was reacted with an azide salt, such as lithium orsodium azide in suitable solvent at a suitable reaction temperature.Suitable solvents for use in the above process included, but were notlimited to, alcoholic solvents such as ethanol, butanol and the like,esters such as ethyl acetate, methyl acetate and the like, DMF,acetonitrile, acetone DMSO. If desired, mixtures of these solvents wereused. The preferred solvents were acetone and DMF. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 40° C. and about 95° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Alternatively, where X¹²=mono- ordi-protected amino, compounds of Formula VIII-W were reacted withsuitably protected amines where the protecting group is chosen such thatthe nucleophilic nature of the nitrogen is either retained or where itcan be enhanced by the action of a reagent such as a base. Those skilledin the art will recognize that such protecting groups include, but arenot limited to, benzyl, trityl, allyl, and alkyloxycarbonyl derivativessuch as BOC, CBZ and FMOC.

Compounds of Formula VIII-W where A¹²=halogen, are prepared fromcompounds of Formula XI-W. In a typical procedure, compounds of FormulaXI-W are treated with halogenating reagents such as but not limited toN-iodosuccinimide, N-bromosuccinirnide, N-chlorosuccinimide, cyanuricchloride, N,N′-1,3-dibromo-5,5-dimethylhydantoin, bromine and iodine,preferably in the presence of one or more radical sources such asdibenzoyl peroxide, azobisisobutyronitrile or light in suitable solventat a suitable reaction temperature. Suitable solvents for use in theabove process included, but were not limited to, chlorinated solventssuch as carbon tetrachloride, dichloromethane, α,α,α-trifluorotolueneand the like, esters such as methyl formate, methyl acetate and thelike, DMF, acetonitrile. If desired, mixtures of these solvents wereused. The preferred solvents were carbon tetrachloride andα,α,α-trifluorotoluene. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired.

Those skilled in the art will appreciate that compounds of Formula IX-Wcan be made by routes disclosed in the literature, for example as inBulletin de la Societe Chimique de France, (1973), (6)(Pt. 2), 2126.

Compounds of Formula I-AQ and/or their precursors may be subjected tovarious functional group interconversions as a means to access somefunctionalities that may not be introduced directly as a result ofincompatible chemistries. Examples of such functional groupmanipulations applicable to compounds of Formula I-AQ and theirprecursors are similar, but not limited to, those described in theprevious schemes that relate to compounds of Formula I-AA, I-R, I-AB,I-AC and I-AQ.

Experimental Procedures 8-Chloro-3-cyclobutyl-imidazo[1,5-a]pyrazine

This compound was prepared using procedures analogous to that describedfor trans-methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate and itsprecursor trans-methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate,using cyclobutanecarboxylic acid in place of4-(methoxycarbonyl)cyclohexanecarboxylic acid.

8-Chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine

8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS(1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Arfor 6 h. The reaction was diluted with DCM (˜400 mL), washed (H₂O,brine), dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the crude material by flash chromatography on silica gel(50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the titlecompound as a pale yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d,J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz,1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100)[MH⁺]; HPLC: t_(R)=3.38 min (OpenLynx, polar_(—)5 min).

3-Cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine

A Parr bomb containing8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine (759 mg, 2.3 mmol) inIPA (100 mL) was saturated with NH₃(g) for 5 min at 0° C. then sealedand heated at 115° C. for 38 h. The reaction mixture was thenconcentrated under reduced pressure, partitioned between DCM (200 mL)and H₂O (50 mL) and extracted with DCM (50 mL). Combined organicfractions were washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to provide the title compound as a white solid; ¹H NMR(400 MHz, CDCl₃) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63(br, 2H), 3.73 (quintetd, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H),2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH⁺]; HPLC: t_(R)=1.75 min(OpenLynx, polar_(—)5 min).

trans-Methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate

trans-Methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate(29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL)and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h.The reaction mixture was concentrated in vacuo, then, the solid residuewas taken up in DCM, then, basified to pH 10 with 2M ammonia inisopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM,and then loaded onto TEA-basified silica gel. The crude product waspurified by a silica gel column chromatography (eluted with 2:3EtOAc/DCM) to obtain the title compound as a yellow powder; ¹H NMR(CDCl₃, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85(ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H),2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt,J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61(d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86)[MH⁺]. HPLC: t_(R)=2.85 min (OpenLynx, polar_(—)5 min).

trans-Methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate

A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid(15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under anitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixturewas cooled to rt, then, (3-chloropyrazin-2-yl)methylaminebis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, thereaction was concentrated in vacuo. The crude reaction mixture waspurified by a silica gel glass column chromatography (eluted with 3:2DCM/EtOAc) to obtain the pure desired product as a slightly yellowishcreamy white powder; ¹H NMR (CDCl₃, 400 MHz) δ 1.43-1.65 (m, 4H),2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, —NH),8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12(84/32) [MH⁺]; HPLC: t_(R)=2.44 min (OpenLynx, polar_(—)5 min).

C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride

A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0g, 36.5 mmmol) in anhydrous CH₂Cl₂ (200 mL) was charged with hydrazine(2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N₂ atmosphere. After2.5 h, MeOH (300 mL) was added and the reaction was heated until thesolution was homogenous. The reaction mixture was allowed to stir for 19h. The white ppt that had formed (2,3-dihydrophthalazine-1,4-dionebyproduct), was filtered off and washed several times with ether. Theclear filtrate was concentrated in vacuo and the concentrate wasdissolved in EtOAc and filtered again to remove white ppt. All solventwas removed, giving a yellow oil, which was dissolved into EtOAc andether and charged with HCl (g). The title compound, a pale yellow solid,instantly precipitated. The title compound was dried in a 40° C. ovenfor 72 h, affording the title compound, as a dark yellow solid; ¹H NMR(400 MHz, CD₃OD) δ 4.55 (2 H, s), 8.27 (1 H, d, J=2.52 Hz), 8.54 (1 H,d, J=2.56 Hz); MS (ES+): m/z 143.96/145.96 (100/60) [MH⁺]; HPLC:t_(R)=0.41 min (OpenLynx, polar_(—)7 min).

7-Cyclobutyl-5-iodoimidazo [5,1-f][1,2,4]triazin-4-ylanmine

To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrouspyridine (10 mL) was added phosphorus oxychloride (POCl₃) (0.578 mL,6.20 mmol) and stirred at rt for 15 min. This mixture was dropwisecharged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3Himidazo[5,1f][1,2,4]triazin-4-one (0.653 mg, 2.07 mmol) in anhydrouspyridine (14 mL) and stirred for 1.5 h. The reaction mixture was cooledto 0° C. quenched with 2M NH₃ in isopropanol (IPA) until basic thenallowed to reach rt and stirred for an additional 2 h. The reactionmixture was filtered through a fritted Buchner funnel and washed withDCM. The filtrate was concentrated in vacuo and purified bychromatography on silica gel [eluting with 30% EtOAc in DCM] resultingin the title compound as an off-white solid; ¹H NMR (CDCl₃, 400 MHz) δ1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m,2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH⁺],HPLC: t_(R)=2.59 min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-5-iodo-3H-imidazo[5,1-f[]1,2,4]triazin-4-one

A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789mg, 4.15 mmol) and N-iodosuccinimide (NIS, 933 mg, 4.15 mmol) inanhydrous DMF (40 mL) was stirred overnight at rt. An additional 4 eq.of NIS was added and reaction was heated to 55° C. for 6 h. The reactionmixture was concentrated in vacuo and partitioned between DCM and H₂Oand separated. The aqueous layer was washed with DCM (3×) and thecombined organic fractions were washed with 1M sodium thiosulfate(Na₂S₂O₃) (1×), brine (1×), dried over sodium sulfate (Na₂SO₄),filtered, and concentrated in vacuo. The solid was triturated with 20%EtOAc in DCM and filtered through a fritted Buchner funnel resulting inthe title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m,1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH⁺], HPLC: t_(R)=2.62min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

A crude solution of cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide (1.33 g, 6.39 mmol)in phosphorus oxychloride (POCl₃) (10 mL) was heated to 55° C. Thereaction was heated for 2 h then concentrated in vacuo and the crude oilwas cooled to 0° C. in an ice-bath and quenched with 2M NH₃ inispropanol (IPA) until slightly basic. This crude reaction mixture wasconcentrated in vacuo and was partitioned between DCM and H₂O andseparated. The aqueous layer was extracted with DCM (3×) and thecombined organic fractions were dried over sodium sulfate (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified bychromatography on silica gel [eluting with 5% MeOH in DCM], resulting inthe title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m,1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z191.27 (100) [MH⁺], HPLC: t_(R)=2.06 min (MicromassZQ, polar_(—)5 min).

Cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide

To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96mmol) and N,N-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) inanhydrous N,N-dimethylforamide (DMF) (20 mL) and anhydrous pyridine (2mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL,3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5h. The reaction mixture was quenched with H₂O (2 mL) and concentrated invacuo and was purified by chromatography on silica gel [eluting with 5%MeOH in DCM (200 mL)→10% MeOH in DCM (800 mL)], affording the titlecompound; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m,1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d,2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100)[MH⁺], HPLC: t_(R)=1.56 min (MicromassZQ, polar_(—)5 min).

6-Aminomethyl-4H-[1,2,4]triazin-5-one

A slurry of2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione (4 g,15.6 mmol) in DCM/EtOH (1:1) (150 mL) was charged with anhydroushydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reactionmixture was concentrated in vacuo and the off-white solid was trituratedwith warm CHCl₃ and filtered through a fritted funnel. The solid wasthen triturated with hot boiling methanol (MeOH) and filtered through afritted funnel resulting in an off-white solid. The material wastriturated a second time as before and dried overnight resulting in thetitle compound as a white solid, which was taken on to the next stepwithout further purification; ¹H NMR (DMSO-d₆, 400 MHz) δ 3.88 (s, 2H),8.31 (2, 1H); MS (ES+): m/z 127.07 (100) [MH⁺], HPLC: t_(R)=0.34 min(MicromassZQ, polar_(—)5 min).

2-(5-Oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione

A slurry of2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione(1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess Raney Ni (3spatula) and heated to reflux for 2 h. The reaction mixture was filteredhot through a small pad of celite and washed with a hot mixture ofEtOH/THF (1:1) (100 mL) and the filtrate was concentrated in vacuoresulting in the title compound as an off-white solid; ¹H NMR (DMSO-d₆,400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS (ES+): m/z257.22 (100) [MH⁺], HPLC: t_(R)=2.08 min (MicromassZQ, polar_(—)5 min).

2-(5-Oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)indan-1,3-dione

A slurry of 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-oxo-propionic acidethyl ester (20 g, 76.6 mmol) in anhydrous EtOH (300 mL) was chargedwith thiosemicarbazide (6.98 g, 76.6 mmol) in one portion and heated to80° C. for 2 h. The reaction mixture was charged withN,N-diisopropylethylamine (DIEA) (26.7 mL, 76.56 mmol) and heated to 40°C. for 6 h then stirred at rt for an additional 10 h. The reactionmixture was concentrated in vacuo and solid was triturated with hotEtOH/EtOAc filtered and washed with EtOAc. The solid was dried overnightin a vacuum oven (40° C.) resulting in the title compound as anoff-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 4.68 (s, 2H), 7.85-7.95 (m,4H); MS (ES+): m/z 289.2 (100) [MH⁺], HPLC: t_(R)=2.50 min (MicromassZQ,polar_(—)5 min).

Benzyl4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-1-carboxylate

A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride(2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) inDCM (27.0 mL) was treated with andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.2 g,0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol).The mixture was stirred at rt overnight then diluted with DCM (30 mL),washed with sat. NaHCO₃ (20 mL) and brine (20 mL), then dried overNa₂SO₄ and concentrated in vacuo. The crude material thus obtained waschromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding3.38 g of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 1.68-1.78 (m,2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m,2H), 4.70 (d, J=4.8 Hz, 2H). 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m,5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z389.17 [MH+].

Benzyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

To a suspension of benzyl4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-1-carboxylate(0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. wasslowly added POCl₃ (0.082 mL, 0.88 mmol). After stirring at rt for anhour the mixture was cooled to 0° C. then treated with solid NaHCO₃. Themixture was stirred for 20 min at rt, diluted with water and extractedwith EtOAc (3×20 mL). The combined extracts were washed with water (2×30mL) and brine (30 mL), then dried over Na₂SO₄, and concentrated in vacuoto yield 2.07 g of desired product. ¹H NMR (400 MHz, CDCl₃): δ 1.98-2.04(m, 4H), 3.03-3.20 (m, 3H), 4.30-4.33 (m, 2H), 5.16 (s, 2H), 7.33 (d,J=5.2 Hz, 1H), 7.35-7.38 (m, 5H), 7.26 (d, J=4.4 Hz, 1H), 7.79 (s, 1H).MS (ES^(+): m/z) 371.22 [MH+].

Benzyl4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

To a solution of benzyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.31 g,0.00354 mol) in DMF (0.6 mL) was added NIS (1.6 g, 0.0071 mol). Thereaction mixture was left to stir at 55° C. for 20 h. then the mixturewas diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine,then dried over Na₂SO₄ and concentrated in vacuo. The crude reactionmixture was chromatographed over silica gel eluting withhexane→hexane:EtOAc 1:1 yielding 1.63 g of desired product. ¹H NMR (400MHz, CDCl₃): δ 1.95-2.04 (m, 4H), 3.02-3.15 (m, 3H), 4.29-4.32 (m, 2H),5.15 (s, 2H), 7.32 (d, J=5.2 Hz, 1H), 7.34-7.37 (m, 5H), 7.66 (d, J=5.2Hz, 1H), MS (ES+): m/z 497.03 [MH+].

Benzyl4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

A mixture of benzyl4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate(0.500 g, 0.00101 mol) in IPA (20 mL) was cooled to at −78° C. andtreated with a stream of ammonia gas over 3 minutes. The resultingsolution was heated at 110° C. in a Parr vessel prior to concentrationin vacuo, suspension in DCM and filtration through a bed of Celite. Thefiltrate was concentrated in vacuo to afford 0.504 g of desired product.¹H NMR (400 MHz, CDCl₃): δ 1.88-2.02 (m, 2H), 2.99-3.10 (m, 3H),4.24-4.41 (m, 2H), 5.15 s, 2H), 6.03 (br, 2H), 7.03 (d, J=4.8 Hz, 1H),7.24 (d, J=5.2 Hz, 1H), 7.31-7.40 (m, 5H). MS (ES+): m/z 479.33 [MH+].

EXAMPLE 1

3-Cyclobutyl-1-(phenylethynyl)imidazo[1,5-a]pyrazin-8-amine

A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg,0.159 mmol) in N,N-dimethylformamide (6 mL) and evacuated and chargedwith N₂ three times, then treated with triethylamine (0.044 mL, 0.318mmol), phenylacetylene (0.175 mL, 1.59 mmol), and copper (I) iodide (3.0mg, 0.0159 mmol). The mixture re-evacuated and charged with N₂ twicemore, then charged with tetrakis(triphenylphoshine)palladium (0) (20.2mg, 0.0175 mmol) and evacuated and charged with N₂ a final two times.The reaction mixture was stirred at rt for 16 h, then concentrated invacuo, dissolved in MeOH/CH₃CN (1:1)(4 mL) and was filtered through a0.45 fritted μM autovial prior to purification via mass directedpreparative HPLC that afforded 13 mg of the title compound. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.87-1.99 (m, 1H), 2.01-2.15 (m, 1H), 2.32-2.47 (m,4H), 3.87-3.99 (m, 1H), 6.66 (brs, 2H), 7.08 (brs, 1H), 7.40-7.51 (m,4H), 7.59-7.67 (m, 2H); MS (ES+): m/z 289.13 [MH⁺].

EXAMPLE 2

1-[(3-Chlorophenyl)ethynyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described for Example 1 using theappropriate acetylene derivative in place of phenylacetylene. MS (ES+):m/z 323.06 & 325.02 [MH⁺].

EXAMPLE 3

1-[(4-Chlorophenyl)ethynyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described for Example 1 using theappropriate acetylene derivative in place of phenylacetylene. MS (ES+):m/z 322.99 & 324.95 [MH⁺].

EXAMPLE 4

1-[(2-Chlorophenyl)ethynyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described for Example 1 using theappropriate acetylene derivative in place of phenylacetylene. MS (ES+):m/z 323.06 & 325.02 [MH⁺].

EXAMPLE 5

3-Cyclobutyl-1-(pyridin-2-ylethynyl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described for Example 1 using theappropriate acetylene derivative in place of phenylacetylene. MS (ES+):m/z 290.10 [MH⁺].

EXAMPLE 6

3-Cyclobutyl-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described for Example 1 using theappropriate acetylene derivative in place of phenylacetylene. MS (ES+):m/z 290.11 [MH⁺].

EXAMPLE 7

7-Cyclobutyl-5-(phenylethynyl)imidazo[5,1-f][1,2,4]triazin-4-amine

Prepared according to the procedure described for Example 1 using7-cyclobutyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-ylamine in place of3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine-8-amine. ¹H NMR (DMSO-d₆, 400MHz) δ 1.88-1.99 (m, 1H ), 2.01-2.10 (m, 1H), 2.29-2.48 (m, 4H),3.93-4.05 (m, 1H), 6.94 (brs, 1H), 7.43-7.48 (m, 3H), 7.66-7.73 (m, 2H),7.92 (s, 1H), 8.55 (brs, 1H); MS (ES+): m/z 290.10 [MH⁺].

EXAMPLE 8

3-Cyclobutyl-1-[(E)-2-phenylvinyl]imidazo[1,5-a]pyrazin-8-amine

A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg,0.159 mmol), styrene (0.022 mL, 0.191 mmol) and triethylamine (0.044 mL,0.318 mmol) in DMF (3.0 mL) was degassed three times, charged withtetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0159 mmol) degassedtwice more and then heated at 75° C. for 16 h. The reaction mixture wasthen concentrated in vacuo dissolved in MeOH/CH₃CN (1:1)(4 mL) and wasfiltered through a 0.45 μM fritted autovial prior to purification viamass directed preparative HPLC which afforded the title compound. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.87-1.99 (m, 1H), 2.02-2.17 (m, 1H), 2.37-2.47 (m,4H), 3.18 (s, 2H), 3.83-3.94 (m, 1H), 6.94 (d, J=4.9 Hz, 1H), 7.25 (t,J=7.33 Hz, 1H), 7.32-7.40 (m, 3H), 7.45 (d, J=15.5 Hz, 1H), 7.63 (d,J=15.45 Hz, 1H), 7.73 (d, J=7.46 Hz, 2H); MS (ES+): m/z 291.15 [MH³⁰ ].

EXAMPLE 9

Benzyl4-(8-amino-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

To a solution of on benzyl4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate(1.00 g, 0.00210 mol) in DMF (26 mL) was added triethylamine (0.58 mL,0.0042 mol), 3-ethynylpyridine (1.1 g, 0.010 mol), and copper(I) iodide(66.6 mg, 0.350 mmol). The mixture was degassed three times, chargedwith tetrakis(triphenylphosphine)palladium(0) (360 mg, 0.00031 mol),degassed again three times and then stirred at rt for 16 h. The reactionmixture was passed through a pad of Celite and the filtrate concentratedin vacuo. The residue was reconstituted in DCM and purified bychromatography over silica get eluting with 20% CH₃CN in DCM to affordthe title compound. ¹H NMR (400 MHz-DMSO-d6) δ 1.62-1.72 (m, 2H),1.91-1.96 (m, 2H), 3.00-3.06 (m, 2H), 3.35-3.42 (m, 1H), 4.08-4.11 (m,2H), 5.11 (s, 2H) 6.69 (bs, 2H), 7.12 (d, J=5.2 Hz, 1H), 7.30-7.33 (m,1H), 7.38-7.40 (m, 4H), 7.46 (m, 1H), 7.74 (d, J=4.8 Hz, 1H), 8.03-8.06(m, 1H), 8.58 (dd, J=1.6, 4.8, 1H) and 8.81-8.82 (m, 1H); MS (ES+): m/z:452.91 [MH+].

EXAMPLE 10

1-(Pyridin-3-ylethynyl)-3-[1-(3-thienylcarbonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Concentrated HCl (10 mL, 10M, 0.3 mol) was added to benzyl4-(8-amino-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate(650 mg, 0.0014 mol) and the mixture was left to stir at rt overnightprior to dilution with with water (30 mL) and washing with diethyl ether(3×20 mL). The aqueous layer was concentrated in vacuo, to afford3-piperidin-4-yl-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-8-aminehydrochloride (610 mg, 99%).

This material (100.00 mg, 0.23 mmol) in DMF (4 mL) was treated withthiophene-3-carboxylic acid (36 mg, 0.28 mmol), TBTU (90.1 mg, 0.28mmol) and DIPEA (0.2 mL, 1 mmol). The mixture was left to stir at rt for30 min then diluted with DCM (30 mL) and washed with water (3×20 mL).The organic extracts were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waschromatographed over silica gel eluting with 5% MeOH in DCM to affordthe title compound.

¹H NMR (400 MHz-DMSO-d6) δ 1.63-1.69 (m, 4H), 1.74-1.77 (m, 4H),3.48-3.50 (m, 1H), 6.70 (bs, 12), 7.13 (d, J=5.2 Hz, 1H), 7.23 (dd,J=1.2, 4.8 Hz, 1H), 7.46-7.50 (m, 1H), 7.61-7.63 (m, 1H), 7.77 (d, J=5.2Hz, 1H), 7.81-7.82 (m, 1H), 8.03-8.06 (m, 1H), 8.59 (dd, J=1.2, 4.8 Hz,1H) and 8.81-8.82 (m, 1H); MS (ES+): m/z: 428.83 [MH+].

1. A compound represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X₁, and X₂ areeach independently N or C-(E¹)_(aa); X₅ is N, C-(E¹)_(aa), orN-(E¹)_(aa); X₃, X₄, X₆, and X₇ are each independently N or C; whereinat least one of X₃, X₄, X₅, X₆, and X₇ is independently N orN-(E¹)_(aa); R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,aminomethylcycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heterocyclyl or heterobicycloC₅₋₁₀alkyl any ofwhich is optionally substituted by one or more independent G¹¹substituents; Q¹ is -A-(K)_(m) A is vinyl or acetylenyl K isindependently, hydrogen, —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen,oxo, aryl (optionally substituted with 1 or more R³¹ groups), hetaryl(optionally substituted with 1 or more R³¹ groups), C₀₋₆alkyl,—C₀₋₈alkylC₃₋₈cycloalkyl, —C₀₋₈alkyl-NR³¹¹S(O)₀₋₂R³²¹,—C₀₋₈alkyl-NR³¹¹S(O)₀₋₂NR³²¹R³³¹, —C₀₋₈alkyl-NR³¹¹CO₂R³²¹,—C₀₋₈alkyl-CON(R³¹¹) S(O)₀₋₂R³²¹, —C₀₋₈alkyl-S(O)₀₋₂NR³¹¹R³²¹,—C₀₋₈alkyl-NR³¹¹COR³²¹, —C₀₋₈alkyl-NR³¹¹CONR³²¹R³³¹,—C₀₋₈alkyl-CONR³¹¹R³²¹, —C₀₋₈alkyl-CO₂R³¹¹, —C₀₋₈alkyl-COR³¹¹,—C₀₋₈alkylS(O)₀₋₂R³¹¹, —C₀₋₈alkyl-O—C₁₋₈alkyl,—C₀₋₈alkyl-O—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈-alkyl-O—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-O—C₀₋₈alkylaryl,—C₀₋₈alkyl-O—C₀₋₈alkylhetaryl, —C₀₋₈alkylaryl, —C₀₋₈alkylhetaryl,—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkyl,—C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-NR³¹¹R³²¹, —C₂₋₈alkenyl, —C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃,OCHF₂; R³¹, R³², R³³, R³¹¹, R³²¹, R³³¹, R³¹², R³²², R³³², R³⁴¹, R³¹³,R³²³, R³³³, and R³⁴², in each instance, is independently C₀₈alkyloptionally substituted with 1-6 independent aryl, cyclyl, heterocyclyl,hetaryl, halo, —CON(C₀₋₈alkyl)(C₀₋₈alkyl), —CO(C₀₋₈alkyl), —OC₀₋₈alkyl,—Oaryl, —Ohetaryl, —Oheterocyclyl, —S(O)₀₋₂aryl, —S(O)₀₋₂hetaryl,—S(O)₀₋₂heterocyclyl, —S(O)₀₋₂C₀₋₈alkyl, —N(C₀₋₈alkyl)(C₀₋₈alkyl),—N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl), —N(C₀₋₈alkyl)CO(C₁₋₈alkyl),—N(C₀₋₈alkyl)CO(C₃₋₈cycloalkyl), —N(C₀₋₈alkyl)CO₂(C₁₋₈alkyl),—S(O)₁₋₂N(C₀₋₈alkyl)C₀₋₈alkyl), —NR¹¹S(O)₁₋₂(C₀₋₈alkyl),—CON(C₃₋₈cycloalkyl)(C₃₋₈cycloalkyl), —CON(C₀₋₈alkyl)(C₃₋₈cycloalkyl),—N(C₃₋₈cycloalkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),—N(C₃₋₈cycloalkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),—N(C₀₋₈alkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),—N(C₀₋₈alkyl)CO₂(C₃₋₈cycloalkyl), —N(C₃₋₈cycloalkyl)CO₂(C₃₋₈cycloalkyl),S(O)₁₋₂N(C₀₋₈alkyl)(C₃₋₈cycloalkyl), —NR¹¹S(O)₁₋₂(C₃₋₈cycloalkyl),C₂₋₈alkenyl, C₂₋₈alkynyl, CN, CF₃, OH, or optionally substituted arylsubstituents; such that each of the above aryl, heterocyclyl, hetaryl,alkyl or cycloalkyl groups may be optionally, independently substitutedwith —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen, oxo, aryl, hetaryl,C₀₋₆alkyl, C₀₋₈alkylcyclyl, —C₀₋₈alkyl-N(C₀₋₈alkyl)—S(O)₀₋₂—(C₀₋₈alkyl),—C₀₋₈alkyl-S(O)₀₋₂—N(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO—N(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-CO—N(C₀₋₈alkyl)(C₀₋₈alkyl), —C₁₋₈alkyl-CO₂—C₀₋₈alkyl),—C₀₋₈alkylS(O)₀₋₂—(C₀₋₈alkyl), —C₀₋₈alkyl-O—C₁₋₈alkyl,—C₀₋₈alkyl-O—C₀₋₈alkylcyclyl, —C₀₋₈alkyl-O—C₀₋₈alkylheterocyclyl,—C₀₋₈alkyl-O—C₀₋₈alkylaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-S—C₀₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylcyclyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylcyclyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocyclyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl, C₂₋₈alkenyl, C₂₋₈alkynyl, NO₂,CN, CF₃, OCF₃, OCHF₂, —C₀₋₈alkyl-C₃₋₈cycloalkyl, —C₀₋₈alkyl-O—C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl), —C₀₋₈alkyl-S(O)₀₋₂—C₀₋₈alkyl, orheterocyclyl optionally substituted with 1-4 independent C₀₋₈alkyl,cyclyl, or substituted cyclyl substituents; E¹ in each instance isindependently halo, —CF₃, —OCF₃, —OR², —NR³¹R³², —C(═O)R³¹, —CO₂R³¹,—CONR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —S(O)₀₋₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³¹)SR³¹,—OC(═C)OR³¹, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —SC(═O)NR³¹R³²,C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —C₁₋₁₀alkoxyC₁₋₁₀alkyl,—C₁₋₁₀alkoxyC₂₋₁₀alkenyl, —C₁₋₁₀alkoxyC₂₋₁₀alkynyl,—C₁₋₁₀alkylthioC₁₋₁₀alkyl, —C₁₋₁₀alkylthioC₂₋₁₀alkenyl,—C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,—cycloC₃₋₈alkylC₁₋₁₀alkyl, -cycloC₃₋₈alkenylC₁₋₁₀alkyl,-cycloC₃₋₈alkylC₂₋₁₀alkenyl, -cycloC₃₋₈alkenylC₂₋₁₀alkenyl,-cycloC₃₋₈alkylC₂₋₁₀alkynyl, -cycloC₃₋₈alkenylC₂₋₁₀alkeynyl,-heterocyclyl-C₀₋₁₀alkyl, -heterocyclyl-C₂₋₁₀alkenyl, or-heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(═O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —NO₂, —CN, —S(═O)₀₋₂R³¹, —SO₂NR³¹,—NR³¹C(═O)R³², —NR³¹C(═O)OR³¹, —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³¹,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, or —SC(═O)NR³¹R³² substituents; or E¹ in each instance isindependently aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, wherethe attachment point is from either the left or right as written, whereany of which is optionally substituted with one or more independenthalo, —CF₃, —OCF₃, —OR³¹ , —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—NO₂, —CN, —S(O)₀₋₂R³¹, —S(O)₀₋₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, or —SC(═O)NR³¹R³²substituents; in the cases of —NR³¹R³², —NR³¹¹R³²¹, —NR³¹²R³²²,—NR³³²R³⁴¹, —NR³¹³R³²³, and —NR³²³R³³³, the respective R³¹ and R³², R³¹¹and R³²¹, R³¹² and R³²², R³³¹ and R³⁴¹, R³¹³ and R³²³, and R³²³ and R³³³are optionally taken together with the nitrogen atom to which they areattached to form a 3-10 membered saturated or unsaturated ring; whereinsaid ring in each instance independently is optionally substituted byone or more independent —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen,oxo, aryl, hetaryl, C₀₋₆alkyl, —C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂N(C₀₋₈alkyl)( C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO₂(C₀₋₈alkyl),—C₀₋₈alkyl-CON((C₀₋₈alkyl))S(O)₀₋₂(C₀₋₈alkyl),—C₀₋₈alkyl-S(O)₀₋₂N(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-CON(C₀₋₈alkyl)(C₀₋₈alkyl), —C₀₋₈alkyl-CO₂(C₀₋₈alkyl),—C₀₋₈alkylS(O)₀₋₂(C₀₋₈alkyl), —C₀₋₈alkyl-O—C₀₋₈alkyl,—C₀₋₈alkyl-O—C₀₋₈alkylcyclyl, —C₀₋₈alkyl-O—C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-O—C₀₋₈alkylaryl, —Oaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-S—C₀₋₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl,—C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl), C₂₋₈alkenyl, C₂₋₈alkynyl, NO₂, CN,CF₃, OCF₃, or OCHF₂substituents; wherein said ring in each instanceindependently optionally includes one or more heteroatoms other than thenitrogen; m is 0, 1, 2,or 3; aa is 0 or 1; and provided that thecompound is not3-cyclobutyl-1-[(4-phenoxyphenyl)ethynyl]imidazo[1,5-a]pyrazin-8-amine,3-cyclobutyl-1-[(1-methyl-1H-imidazol-5-yl)ethynyl]imidazo[1,5-a]pyrazin-8-amine,N-{3-[(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)ethynyl]phenyl}-4-chlorobenzamideor 3-cyclobutyl-1-(pyridin-4-ylethynyl)imidazo[1,5-a]pyrazin-8-amine. 2.The compound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇are C.
 3. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄,X₆ and X₇ are C.
 4. The compound according to claim 1, consisting of

or a pharmaceutically acceptable salt thereof.
 5. A compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 6. Acomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof; and an anti-neoplastic,anti-tumor, anti-angiogenic, or chemotherapeutic agent.
 7. A compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a cytotoxic or angiogenesis inhibitingcancer therapeutic agent.
 8. A method of treatment of hyperproliferativedisorder comprising a step of administering an effective amount of thecompound according to claim 1, or a pharmaceutically acceptable saltthereof.
 9. The method of treatment according to claim 8, wherein thehyperproliferative disorder is breast cancer, lung cancer, non-smallcell lung cancer, kidney cancer, renal cell carcinoma, prostate cancer,cancer-of the blood, liver cancer, ovarian cancer, thyroid cancer,&endometrial cancer, cancer of the GI tract, lymphoma, renal cellcarcinoma, mantle cell lymphoma, or endometrial cancer.
 10. A method oftreatment of rheumatoid arthritis, hamartoma syndromes, transplantrejection, atherosclerosis, IBD, multiple sclerosis or immunosuppressiondiseases comprising a step of administering an effective amount of thecompound according to claim 1, or a pharmaceutically acceptable saltthereof.